2-(piperidin-1-yl)-4-heterocyclyl-thiazole-5-carboxylic acid derivatives against bacterial infections

ABSTRACT

Compounds of formula (I) and their pharmaceutically acceptable salts are described. Processes for their preparation, pharmaceutical compositions containing them, their use as medicaments and their use in the treatment of bacterial infections are also described.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Application No.61/121,953, Attorney Docket No. 103596-1L, filed on Dec. 12, 2008; theentire contents of which is hereby expressly incorporated by referencein its entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that demonstrateantibacterial activity, processes for their preparation, pharmaceuticalcompositions containing them as the active ingredient, to their use asmedicaments and to their use in the manufacture of medicaments for usein the treatment of bacterial infections in warm-blooded animals such ashumans. In particular this invention relates to compounds useful for thetreatment of bacterial infections in warm-blooded animals such ashumans, more particularly to the use of these compounds in themanufacture of medicaments for use in the treatment of bacterialinfections in warm-blooded animals such as humans.

BACKGROUND OF THE INVENTION

The international microbiological community continues to express seriousconcern that the evolution of antibiotic resistance could result instrains against which currently available antibacterial agents will beineffective. In general, bacterial pathogens may be classified as eitherGram-positive or Gram-negative pathogens. Antibiotic compounds witheffective activity against both Gram-positive and Gram-negativepathogens are generally regarded as having a broad spectrum of activity.

Gram-positive pathogens, for example Staphylococci, Enterococci,Streptococci and mycobacteria, are particularly important because of thedevelopment of resistant strains which are both difficult to treat anddifficult to eradicate from the hospital environment once established.Examples of such strains are methicillin resistant staphylococcus aureus(MRSA), methicillin resistant coagulase negative staphylococci (MRCNS),penicillin resistant Streptococcus pneumoniae and multiple resistantEnterococcus faecium.

The preferred clinically effective antibiotic for treatment of lastresort of such resistant Gram-positive pathogens is vancomycin.Vancomycin is a glycopeptide and is associated with various toxicities,including nephrotoxicity. Furthermore, and most importantly,antibacterial resistance to vancomycin and other glycopeptides is alsoappearing. This resistance is increasing at a steady rate renderingthese agents less and less effective in the treatment of Gram-positivepathogens. There is also now increasing resistance appearing towardsagents such as β-lactams, quinolones and macrolides used for thetreatment of upper respiratory tract infections, also caused by certainGram negative strains including H. influenzae and M. catarrhalis.

Consequently, in order to overcome the threat of widespread multi-drugresistant organisms, there is an on-going need to develop newantibiotics, particularly those with either a novel mechanism of actionand/or containing new pharmacophoric groups.

Deoxyribonucleic acid (DNA) gyrase is a member of the type II family oftopoisomerases that control the topological state of DNA in cells(Champoux, J. J.; 2001. Ann. Rev. Biochem. 70: 369-413). Type IItopoisomerases use the free energy from adenosine triphosphate (ATP)hydrolysis to alter the topology of DNA by introducing transientdouble-stranded breaks in the DNA, catalyzing strand passage through thebreak and resealing the DNA. DNA gyrase is an essential and conservedenzyme in bacteria and is unique among topoisomerases in its ability tointroduce negative supercoils into DNA. The enzyme consists of twosubunits, encoded by gyrA and gyrB, forming an A₂B₂ tetrameric complex.The A subunit of gyrase (GyrA) is involved in DNA breakage and resealingand contains a conserved tyrosine residue that forms the transientcovalent link to DNA during strand passage. The B subunit (GyrB)catalyzes the hydrolysis of ATP and interacts with the A subunit totranslate the free energy from hydrolysis to the conformational changein the enzyme that enables strand-passage and DNA resealing.

Another conserved and essential type II topoisomerase in bacteria,called topoisomerase IV, is primarily responsible for separating thelinked closed circular bacterial chromosomes produced in replication.This enzyme is closely related to DNA gyrase and has a similartetrameric structure formed from subunits homologous to Gyr A and to GyrB. The overall sequence identity between gyrase and topoisomerase IV indifferent bacterial species is high. Therefore, compounds that targetbacterial type II topoisomerases have the potential to inhibit twotargets in cells, DNA gyrase and topoisomerase IV; as is the case forexisting quinolone antibacterials (Maxwell, A. 1997, Trends Microbiol.5: 102-109).

DNA gyrase is a well-validated target of antibacterials, including thequinolones and the coumarins. The quinolones (e.g. ciprofloxacin) arebroad-spectrum antibacterials that inhibit the DNA breakage and reunionactivity of the enzyme and trap the GyrA subunit covalently complexedwith DNA (Drlica, K., and X. Zhao, 1997, Microbiol. Molec. Biol. Rev.61: 377-392). Members of this class of antibacterials also inhibittopoisomerase IV and as a result, the primary target of these compoundsvaries among species. Although the quinolones are successfulantibacterials, resistance generated by mutations in the target (DNAgyrase and topoisomerase IV) is becoming an increasing problem inseveral organisms, including S. aureus and Streptococcus pneumoniae(Hooper, D. C., 2002, The Lancet Infectious Diseases 2: 530-538). Inaddition, quinolones, as a chemical class, suffer from toxic sideeffects, including arthropathy that prevents their use in children(Lipsky, B. A. and Baker, C. A., 1999, Clin. Infect. Dis. 28: 352-364).Furthermore, the potential for cardiotoxicity, as predicted byprolongation of the QT_(c) interval, has been cited as a toxicityconcern for quinolones.

There are several known natural product inhibitors of DNA gyrase thatcompete with ATP for binding the GyrB subunit (Maxwell, A. and Lawson,D. M. 2003, Curr. Topics in Med. Chem. 3: 283-303). The coumarins arenatural products isolated from Streptomyces spp., examples of which arenovobiocin, chlorobiocin and coumermycin A1. Although these compoundsare potent inhibitors of DNA gyrase, their therapeutic utility islimited due to toxicity in eukaryotes and poor penetration inGram-negative bacteria (Maxwell, A. 1997, Trends Microbiol. 5: 102-109).Another natural product class of compounds that targets the GyrB subunitis the cyclothialidines, which are isolated from Streptomyces filipensis(Watanabe, J. et al 1994, J. Antibiot. 47: 32-36). Despite potentactivity against DNA gyrase, cyclothialidine is a poor antibacterialagent showing activity only against some eubacterial species (Nakada, N,1993, Antimicrob. Agents Chemother. 37: 2656-2661).

Synthetic inhibitors that target the B subunit of DNA gyrase andtopoisomeraseIV are known in the art. For example, coumarin-containingcompounds are described in patent application number WO99/35155,5,6-bicyclic heteroaromatic compounds are described in patentapplication WO 02/060879, and pyrazole compounds are described in patentapplication WO 01/52845 (U.S. Pat. No. 6,608,087). AstraZeneca has alsopublished certain applications describing anti-bacterial compounds:WO2005/026149, WO2006/087544, WO2006/087548, WO2006/087543,WO2006/092599 and WO2006/092608.

SUMMARY OF THE INVENTION

We have discovered a new class of compounds that are useful forinhibiting DNA gyrase and/or topoisomerase IV. The compounds of thepresent invention are regarded as effective against both Gram-positiveand certain Gram-negative pathogens.

According to the present invention there is provided a compound offormula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is chloro or cyano;

R² is hydrogen, chloro, or cyano;

R³ is halo, C₁₋₄alkyl, C₁₋₄alkoxy, or allyloxy;

R⁴ is hydrogen or C₁₋₄alkyl;

Ring A is selected from formula (a), (b) or (b′):

wherein:

“*” is the point of attachment to the thiazolyl ring;

X is CH, CR⁶, or N;

R⁵ is H, a C₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R⁶, for each occurrence is independently selected from halo, —NR⁷R⁸,—OR⁸, and heterocycle wherein said heterocycle comprises at least onenitrogen ring member and is optionally substituted on one or more carbonatoms with one or more R⁹ and is optionally substituted on one or morering nitrogens with R¹⁰;

R⁶ is hydrogen or R⁶;

R⁷ and R⁸ are each, independently, selected from the group consisting ofhydrogen and a C₁₋₆alkyl wherein said alkyl is optionally substitutedwith one or more independently selected from —OH,N,N-di(C₁₋₄alkyl)amino, a C₁₋₆alkoxy, a C₁₋₆alkoxyC₁₋₆alkoxy, andheterocycle, wherein said heterocycle is optionally substituted on oneor more carbon atoms with one or more independently selected halo,C₁₋₆alkyl, and C₁₋₆alkoxy, and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a C₁₋₄alkyl;

R⁹ is, for each occurrence, is independently selected from a C₁₋₄alkyl,halo, hydroxy, C₁₋₄alkoxy, amino, N—(C₁₋₄alkyl)amino, andN,N-di(C₁₋₄alkyl)amino;

R¹⁰, for each occurrence, is independently selected from a C₁₋₄alkyloptionally substituted with N,N-di(C₁₋₄alkyl)amino, —OH, heterocycle,and C₃₋₆cycloalkyl, wherein the heterocycle may be optionallysubstituted with C₁₋₄alkyl; and

n is 0, 1, 2, or 3.

In another aspect, the present invention provides a compound of formula(I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is chloro or cyano;

R² is hydrogen, chloro, or cyano;

R³ is halo, C₁₋₄alkyl, C₁₋₄alkoxy, or allyloxy;

R⁴ is hydrogen or C₁₋₄alkyl;

Ring A is selected from formula (a) or (b):

wherein:

“*” is the point of attachment to the thiazolyl ring;

X is CH, CR⁶, or N;

R⁵ is H, a C₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl;

R⁶, for each occurrence, is independently selected from halo, —NR⁷R⁸,and heterocycle wherein said heterocycle comprises at least one nitrogenring member and is optionally substituted on one or more carbon atomswith one or more R⁹ and is optionally substituted on one or more ringnitrogens with R¹⁰;

R^(6′) is hydrogen or R⁶;

R⁷ and R⁸ are each, independently, selected from the group consisting ofhydrogen and a C₁₋₆alkyl wherein said alkyl is optionally substitutedwith one or more independently selected —OH, a C₁₋₆alkoxy, aC₁₋₆alkoxyC₁₋₆alkoxy, and heterocycle, wherein said heterocycle isoptionally substituted on one or more carbon atoms with one or moreindependently selected halo, C₁₋₆alkyl, or C₁₋₆alkoxy, and wherein ifsaid heterocyclyl contains an —NH— moiety that nitrogen may beoptionally substituted by a C₁₋₄alkyl;

R⁹ is, for each occurrence, is independently selected from a C₁₋₄alkyl,halo, hydroxy, C₁₋₄alkoxy, amino, N—(C₁₋₄alkyl)amino, andN,N-di(C₁₋₄alkyl)amino;

R¹⁰, for each occurrence, is independently selected from a C₁₋₄alkyl;and

n is 0, 1, 2, or 3.

In certain embodiments of formula (I), n is 1, 2, or 3.

In certain embodiments of formula (I), R⁶, for each occurrence, isindependently selected from —NR⁷R⁸, and heterocycle wherein saidheterocycle comprises at least one nitrogen ring member and isoptionally substituted on one or more carbon atoms with one or more R⁹and is optionally substituted on one or more ring nitrogens with R¹⁰;and R^(6′) is R⁶.

In certain embodiments of formula (I), —OR⁸ is selected from the groupconsisting of hydrogen and a —OC₂₋₆alkyl wherein said alkyl moiety isoptionally substituted with one or more independently selected from —OH,N,N-di(C₁₋₄alkyl)amino, a C₁₋₆alkoxy, a C₁₋₆alkoxyC₁₋₆alkoxy, andheterocycle, wherein said heterocycle is optionally substituted on oneor more carbon atoms with one or more independently selected halo,C₁₋₆alkyl, and C₁₋6alkoxy, and wherein if said heterocyclyl contains an—NH— moiety that nitrogen may be optionally substituted by a C₁₋₄alkyl.In particular embodiments, —OR⁸ is ethoxy optionally substituted asdescribed above.

In another embodiment, the invention provides pharmaceuticalcompositions comprising a compound represented by formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.

In another embodiment, the invention provides a method of inhibitingbacterial DNA gyrase and/or bacterial topoisomerase IV in a warm-bloodedanimal in need of such treatment, comprising administering to the animalan effective amount of a compound represented by formula (I), or apharmaceutically acceptable salt thereof. In a particular embodiment,the warm-blooded animal is a human.

In another embodiment, the invention provides a method of producing anantibacterial effect in a warm-blooded animal in need of such treatment,comprising administering to the animal an effective amount of a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof. In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides a method of treating abacterial infection in a warm-blooded animal in need thereof, comprisingadministering to the animal an effective amount of a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof. In a particular embodiment, the warm-blooded animal is a human.In one embodiment, the bacterial infection is selected from the groupconsisting of community-acquired pneumoniae, hospital-acquiredpneumoniae, skin and skin structure infections, acute exacerbation ofchronic bronchitis, acute sinusitis, acute otitis media,catheter-related sepsis, febrile neutropenia, osteomyelitis,endocarditis, urinary tract infections and infections caused by drugresistant bacteria such as Penicillin-resistant Streptococcuspneumoniae, methicillin-resistant Staphylococcus aureus,methicillin-resistant Staphylococcus epidermidis andVancomycin-Resistant Enterococci. In a particular embodiment, thewarm-blooded animal is a human.

In another embodiment, the invention provides the use of a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use in the productionof an antibacterial effect in a warm-blooded animal. In a particularembodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use in inhibition ofbacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animal.In a particular embodiment, the warm-blooded animal is a human.

In another embodiment, the invention provides the use of a compoundrepresented by formula (I), or a pharmaceutically acceptable saltthereof, for the manufacture of a medicament for use the treatment of abacterial infection in a warm-blooded animal. In one embodiment, thebacterial infection is selected from the group consisting ofcommunity-acquired pneumoniae, hospital-acquired pneumoniae, skin andskin structure infections, acute exacerbation of chronic bronchitis,acute sinusitis, acute otitis media, catheter-related sepsis, febrileneutropenia, osteomyelitis, endocarditis, urinary tract infections,Penicillin-resistant Streptococcus pneumoniae, methicillin-resistantStaphylococcus aureus, methicillin-resistant Staphylococcus epidermidisand Vancomycin-Resistant Enterococci. In a particular embodiment, thewarm-blooded animal is a human.

In another embodiment, the invention provides a compound represented byformula (I), or a pharmaceutically acceptable salt thereof, for use inproduction of an anti-bacterial effect in a warm-blooded animal.

In another embodiment, the invention provides a compound represented byformula (I), or a pharmaceutically acceptable salt thereof, for use ininhibition of bacterial DNA gyrase and/or topoisomerase IV in awarm-blooded animal.

In another embodiment, the invention provides a compound represented byformula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of a bacterial infection in a warm-blooded animal.

In another embodiment, the invention provides a compound represented byformula (I), or a pharmaceutically acceptable salt thereof, for use inthe treatment of community-acquired pneumoniae, hospital-acquiredpneumoniae, skin and skin structure infections, acute exacerbation ofchronic bronchitis, acute sinusitis, acute otitis media,catheter-related sepsis, febrile neutropenia, osteomyelitis,endocarditis, urinary tract infections, Penicillin-resistantStreptococcus pneumoniae, methicillin-resistant Staphylococcus aureus,methicillin-resistant Staphylococcus epidermidis or Vancomycin-ResistantEnterococci.

DETAILED DESCRIPTION OF THE INVENTION

In this specification, the term “alkyl” includes both straight andbranched chain hydrocarbon which are fully saturated. “C₁₋₆” or “C₁₋₄”before a group, such as an alkyl group or an alkoxy group, indicates thenumber of carbon atoms in the group. For example, a “C₁₋₆alkyl” is analkyl groups that has from 1 to 6 carbon atoms. Likewise, a “C₁₋₄alkyl”is an alkyl group that has from 1 to 4 carbon atom. Examples of“C₁₋₄alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl,1-methylpropyl, isobutyl, and t-butyl. References to individual alkylgroups such as propyl are specific for the straight chain version onlyunless otherwise specified. An analogous convention applies to othergeneric terms.

Where optional substituents are chosen from one or more groups it is tobe understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 4-12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂-group canoptionally be replaced by a —C(O)— and a ring sulphur atom may beoptionally oxidised to form the S-oxide(s). In one aspect of theinvention a “heterocyclyl” is a saturated, partially saturated orunsaturated, monocyclic ring containing 5 or 6 atoms of which at leastone atom is chosen from nitrogen, sulphur or oxygen, it may, unlessotherwise specified, be carbon or nitrogen linked, a —CH₂— group canoptionally be replaced by a —C(O)— and a ring sulphur atom may beoptionally oxidised to form the S-oxides. In a further aspect of theinvention a “heterocyclyl” is an unsaturated, carbon-linked, monocyclicring containing 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen. Examples of suitable values of the term“heterocyclyl” are piperazinyl, piperidinyl, morpholinyl,2-oxo-pyrrolidinyl, 1,3-dioxanyl, and 2-oxo-1,3-oxazolidinyl,2-oxo-imidazolidinyl. Further examples of suitable values for the term“heterocyclyl” include pyridinyl, pyrazinyl, imidazolyl, and1,2,4-triazolyl.

An “alkoxy” is an alkyl group that is linked to another moiety via —O—.Examples of “C₁₋₄alkoxy” include methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, and t-butoxy.

An “alkoxyalkyl” is an alkyl group which is substituted with an alkoxygroup.

An “alkoxyalkoxy is an alkoxy group which is substituted with anotheralkoxy group, wherein the alkoxy groups may have the same or a differentnumber of carbon atoms.

An “amino” group is —NH₂. An “N—(C₁₋₄alkyl)amino” is an amino group inwhich on hydrogen is replaced with a C₁₋₄alkyl group. Examples of“N—(C₁₋₄alkyl)amino” groups include methylamino and ethylamino. An“N,N-di(C₁₋₄alkyl)amino” is an amino group in which both hydrogens arereplaced with the same or a different C₁₋₄alkyl group. Examples of“N,N-di(C₁₋₄alkyl)amino” include N,N-dimethylamino, N,N-diethylamino andN-ethyl-N-methylamino.

A compound of formula (I) may form stable acid or basic salts, and insuch cases administration of a compound as a salt may be appropriate,and pharmaceutically acceptable salts may be made by conventionalmethods such as those described following.

Suitable pharmaceutically-acceptable salts include acid addition saltssuch as methanesulfonate, tosylate, α-glycerophosphate, fumarate,hydrochloride, citrate, maleate, tartrate and hydrobromide. Alsosuitable are salts formed with phosphoric and sulfuric acid. In anotheraspect suitable salts are base salts such as an alkali metal salt forexample sodium, an alkaline earth metal salt for example calcium ormagnesium, an organic amine salt for example triethylamine, morpholine,N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine,N,N-dibenzylethylamine, tris-(2-hydroxyethyl)amine, N-methyl d-glucamineand amino acids such as lysine. There may be more than one cation oranion depending on the number of charged functions and the valency ofthe cations or anions. In one aspect of the invention thepharmaceutically-acceptable salt is the sodium salt.

However, to facilitate isolation of the salt during preparation, saltswhich are less soluble in the chosen solvent may be utilised whetherpharmaceutically-acceptable or not.

Within the present invention it is to be understood that a compound ofthe formula (I) or a salt thereof may exhibit the phenomenon oftautomerism and that the formulae drawings within this specification canrepresent only one of the possible tautomeric forms. It is to beunderstood that the invention encompasses any tautomeric form whichinhibits DNA gyrase and/or topoisomerase IV and is not to be limitedmerely to any one tautomeric form utilised within the formulae drawings.The formulae drawings within this specification can represent only oneof the possible tautomeric forms and it is to be understood that thespecification encompasses all possible tautomeric forms of the compoundsdrawn not just those forms which it has been possible to showgraphically herein. The same applies to compound names.

It will be appreciated by those skilled in the art that in addition tothe two asymmetric carbons drawn in formula (I), compounds of formula(I) may contain additional asymmetrically substituted carbon(s) andsulphur atom(s), and accordingly may exist in, and be isolated in, asfar as those additional asymmetrically substituted carbon(s) and sulphuratom(s) are concerned, optically-active and racemic forms at thosepositions. It is to be understood that the present invention encompassesany racemic, optically-active, polymorphic or stereoisomeric form, ormixtures thereof, at any additional asymmetrically substituted carbon(s)and sulphur atom(s), which possesses properties useful in the inhibitionof DNA gyrase and/or topoisomerase IV.

Optically-active forms may be prepared by procedures known in the artfor example, by resolution of the racemic form by recrystallizationtechniques, by synthesis from optically-active starting materials, bychiral synthesis, by enzymatic resolution, by biotransformation, or bychromatographic separation using a chiral stationary phase.

Some compounds may exhibit polymorphism. It is to be understood that thepresent invention encompasses any polymorphic form, or mixtures thereof,which form possesses properties useful in the inhibition of DNA gyraseand/or topoisomerase IV

It is also to be understood that certain compounds of the formula (I)and salts thereof can exist in solvated as well as unsolvated forms suchas, for example, hydrated forms. It is to be understood that theinvention encompasses all such solvated forms which inhibit DNA gyraseand/or topoisomerase IV.

By way of clarity, compounds of the invention included all isotopes ofthe atoms present in formula (I) and any of the examples or embodimentsdisclosed herein. For example, H (or hydrogen) represents any isotopicform of hydrogen including ¹H, ²H (D), and ³H (T); C represents anyisotopic form of carbon including ¹²C, ¹³C, and ¹⁴C; O represents anyisotopic form of oxygen including ¹⁶O, ¹⁷O and ¹⁸O; N represents anyisotopic form of nitrogen including ¹³N, ¹⁴N and ¹⁵N; P represents anyisotopic form of phosphorous including ³¹P and ³²P; S represents anyisotopic form of sulfur including ³²S and ³⁵S; F represents any isotopicform of fluorine including ¹⁹F and ¹⁸F; Cl represents any isotopic formof chlorine including ³⁵Cl, ³⁷Cl and ³⁶Cl; and the like. In a preferredembodiment, compounds represented by formula (I) comprises isotopes ofthe atoms therein in their naturally occurring abundance. However, incertain instances, it is desirable to enrich one or more atom in aparticular isotope which would normally be present in less abundance.For example, ¹H would normally be present in greater than 99.98%abundance; however, a compound of the invention can be enriched in ²H or³H at one or more positions where H is present. In one embodiment, whena compound of the invention is enriched in a radioactive isotope, forexample ³H and ¹⁴C, they may be useful in drug and/or substrate tissuedistribution assays. It is to be understood that the inventionencompasses all such isotopic forms which inhibit DNA gyrase and/ortopoisomerase IV.

Another embodiment of the invention provides a compound selected fromthe group consisting of any one or more of the compounds described inthe Examples section, or a salt, e.g., a pharmaceutically acceptablesalt, thereof. Moreover, if such compound is represented as a salt, thepresent invention is intended to include free bases, free acids, oralternative salts of these particular compounds. Additional embodimentscomprise compositions and medicaments containing the same (including theaforementioned free bases, free acids, or alternative salts), as well asprocesses for the preparation and use of such compounds, compositionsand medicaments. Moreover, it should be noted that each of thesecompounds, and salts thereof, are also intended to be separateembodiments, and in this regard, each species listed in the Examples,and salt thereof, should be considered to be an individual embodiment.

Moreover, it should be understood that the present invention is intendedto include any novel compound or pharmaceutical composition describedherein.

There follow particular and suitable values for certain substituents andgroups referred to in this specification. These values may be used whereappropriate with any of the definitions and embodiments disclosedhereinbefore, or hereinafter. For the avoidance of doubt each statedspecies represents a particular and independent aspect of thisinvention. Unless otherwise stated, variables in the particularembodiments described below are defined as for formula (I).

R¹ is chloro.

R¹ is cyano.

R² is hydrogen.

R² is chloro.

R² is cyano.

R³ is halo.

R³ is fluoro.

R³ is C₁₋₄alkyl.

R³ is methyl.

R³ is ethyl.

R³ is C₁₋₄alkoxy.

R³ is methoxy.

R³ is ethoxy.

R³ is allyloxy.

R³ is methyl, ethoxy, or allyloxy.

R³ is methyl, methoxy, ethoxy, or allyloxy.

R⁴ is hydrogen.

R⁴ is methyl.

R⁴ is ethyl.

Ring A is represented by formula (a):

Ring A is represented by formula (a), and X is CR^(6′).

Ring A is represented by formula (a), and X is N.

Ring A is 1-(2-methoxyethyl)-1H-imidazol-2-yl.

Ring A is 1-methyl-1H-1,2,4-triazol-5-yl.

Ring A is selected from the group consisting of1-(2-methoxyethyl)-1H-imidazol-2-yl or 1-methyl-1H-1,2,4-triazol-5-yl.

Ring A is formula (c):

R⁵ is hydrogen.

R⁵ is C₁₋₄alkyl.

R⁵ is methyl.

R⁵ is C₁₋₄alkoxyC₁₋₄alkyl.

R⁵ is methoxyethyl.

Ring A is represented by formula (b):

Ring A is represented by formula (b) and X is CH or CR⁶.

Ring A is represented by formula (b) and X is N.

Ring A is 3-fluoropyridin-2-yl.

Ring A is pyrazin-2-yl

Ring A is selected from the group consisting of 3-fluoropyridin-2-yl orpyrazin-2-yl.

R⁶ is piperidino.

R⁶ is piperazinyl.

R⁶ is N-methylpiperazino.

R⁶ is morpholino.

R⁶ is piperidino, piperazinyl, N-methylpiperazino or morpholino.

R⁶ is 1-(1H-1,2,3-triazol-5-yl)methanamino.

R⁶ is 2-(2-oxo-pyrrolidino)ethylamino.

R⁶ is 2-methoxyethylamino.

R⁶ is 2-(4-fluoropiperidino)ethylamino.

R⁶ is 1-(1,3-dioxan-4-yl)-N-methylmethanamino.

R⁶ is N-(1-methoxymethyl-2-methoxyethyl)amino.

R⁶ is 2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino.

R⁶ is 2-(2-methoxyethoxy)-ethylamino.

R⁶ is 2-morpholinoethylamino.

R⁶ is 2-(2-oxo-imidazolidin-1-yl)ethylamino.

R^(6′) is hydrogen. P R^(6′) is R⁶.

Ring A is represented by formula (b), X is CH or CR⁶, and R⁶ ispiperidino, piperazinyl, N-methylpiperazino or morpholino.

Ring A is represented by formula (b), X is N, and R⁶ is piperidino,piperazinyl, N-methylpiperazino or morpholino.

Ring A is represented by formula (b), X is CH or CR⁶, n is 1 and R⁶ isselected from 1-(1H-1,2,3-triazol-5-yl)methanamino,2-(2-oxo-pyrrolidino)ethylamino, 2-methoxyethylamino,2-(4-fluoropiperidino)ethylamino,1-(1,3-dioxan-4-yl)-N-methylmethanamino,N-(1-methoxymethyl-2-methoxyethyl)amino,2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino,2-(2-methoxyethoxy)-ethylamino, 2-morpholinoethylamino, or2-(2-oxo-imidazolidin-1-yl)ethylamino.

Ring A is represented by formula (b), n is 1 and R⁶ is selected from1-(1H-1,2,3-triazol-5-yl)methanamino, 2-(2-oxo-pyrrolidino)ethylamino,2-methoxyethylamino, 2-(4-fluoropiperidino)ethylamino,1-(1,3-dioxan-4-yl)-N-methylmethanamino,N-(1-methoxymethyl-2-methoxyethyl)amino,2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino,2-(2-methoxyethoxy)-ethylamino, 4-[2-(diethylamino)ethyl]piperazin-1-yl,2-(4-methylpiperazin-1-yl)ethylamino, 2-(dimethylamino)ethoxy,2-(4-methylpiperazin-1-yl)ethoxy, 2-morpholinoethylamino, or2-(2-oxo-imidazolidin-1-yl)ethylamino.

Ring A is represented by formula (d):

Ring A is represented by formula (e):

Ring A is selected from formula (d) or (e):

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is 1-(2-methoxyethyl)-1H-imidazol-2-yl,1-methyl-1H-1,2,4-triazol-5-yl, 3-fluoropyridin-2-yl or pyrazin-2-yl.

Therefore in a further aspect of the invention there is provided acompound of formula

(I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is formula (c):

wherein:

X is CH or N; and

R⁵ is H, a C₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

X is CH or N; and

R⁶ is a halo.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, methoxy, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is —OR⁸ or —NR⁷R⁸;

R⁷ is hydrogen or a C₁₋₄alkyl; and

R⁸ is selected from the group consisting of1-(1H-1,2,3-triazol-5-yl)methyl, 2-(2-oxo-pyrrolidino)ethyl,2-methoxyethyl, 2-(4-fluoropiperidino)ethyl,1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(dimethylamino)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl,2-(2-methoxyethoxy)-ethyl, 2-morpholinoethyl, or2-(2-oxo-imidazolidin-1-yl)ethyl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, methoxy, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is —NR⁷R⁸;

R⁷ is hydrogen or a C₁₋₄alkyl; and

R⁸ is selected from the group consisting of1-(1H-1,2,3-triazol-5-yl)methyl, 2-(2-oxo-pyrrolidino)ethyl,2-methoxyethyl, 2-(4-fluoropiperidino)ethyl,1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl,2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl, 2-(2-methoxyethoxy)-ethyl,2-morpholinoethyl, or 2-(2-oxo-imidazolidin-1-yl)ethyl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methyl, methoxy, ethoxy, or allyloxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is piperidino, piperazinyl, N-methylpiperazino or morpholino.Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methoxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is —NR⁷R⁸;

R⁷ is hydrogen or a C₁₋₄alkyl; and

R⁸ is selected from the group consisting of1-(1H-1,2,3-triazol-5-yl)methyl, 2-(2-oxo-pyrrolidino)ethyl,2-methoxyethyl, 2-(4-fluoropiperidino)ethyl,1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl,2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl, 2-(2-methoxyethoxy)-ethyl,2-morpholinoethyl, or 2-(2-oxo-imidazolidin-1-yl)ethyl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is hydrogen, chloro or cyano;

R³ is methoxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is piperidino, piperazinyl, N-methylpiperazino or morpholino.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is chloro;

R³ is methoxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is —NR⁷R⁸;

R⁷ is hydrogen or a C₁₋₄alkyl; and

R⁸ is selected from the group consisting of1-(1H-1,2,3-triazol-5-yl)methyl, 2-(2-oxo-pyrrolidino)ethyl,2-methoxyethyl, 2-(4-fluoropiperidino)ethyl,1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl,2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl, 2-(2-methoxyethoxy)-ethyl,2-morpholinoethyl, or 2-(2-oxo-imidazolidin-1-yl)ethyl.

Therefore in a further aspect of the invention there is provided acompound of formula (I) (as depicted above) wherein:

R¹ is chloro;

R² is chloro;

R³ is methoxy;

R⁴ is hydrogen, methyl or ethyl;

Ring A is selected from formula (d) or (e):

wherein:

R⁶ is piperidino, piperazinyl, N-methylpiperazino or morpholino.

Particular compounds of the invention are the compounds of the Examples,each of which provides a further independent aspect of the invention. Infurther aspects, the present invention also comprises any two or morecompounds of the Examples.

In one embodiment of the invention are provided compounds of formula(I). In an alternative embodiment are providedpharmaceutically-acceptable salts of compounds of formula (I).

In a further aspect the present invention provides a process forpreparing a compound of formula (I), or a pharmaceutically-acceptablesalt thereof.

Thus, the present invention also provides that the compounds of theformula (I) and pharmaceutically-acceptable salts thereof, can beprepared by a process as follows (wherein the variables are as definedabove unless otherwise stated):

Process a) reacting a compound of formula (II) or:

or an activated acid derivative thereof; with a compound of formula(III):

orProcess b) reacting a compound of formula (IV):

with a compound of formula (V):

wherein L is a displaceable group; orProcess c) for compounds of formula (I) wherein R⁴ is C₁₋₄alkyl;reacting a compound of formula (I) which is a compound of formula (VI)or (VI'):

with a compound of formula (VII):

R^(4a)—OH  (VII)

wherein R^(4a) is C₁₋₄alkyl;orProcess d) for compounds of formula (I) or wherein R⁴ is hydrogen;deprotecting a compound of formula (VIII):

wherein Pg is a carboxylic acid protecting group, such as a C₁₋₄alkyl;and thereafter if necessary:i) converting a compound of the formula (I) into another compound of theformula (I);ii) removing any protecting groups;iii) forming a pharmaceutically acceptable salt; and/oriv) chirally purifying the compound of formula (I).

L is a displaceable group. Suitable values for L include halo, forexample chloro and bromo, pentafluorophenoxy and2,5-oxopyrrolidin-1-yloxy.

Pg is a carboxylic acid protecting group. Suitable values for Pg aredefined herein below.

Specific reaction conditions for the above reaction are as follows.

Process a) Compounds of formula (II) and (III) may be coupled togetherin the presence of a suitable coupling reagent. Standard peptidecoupling reagents known in the art can be employed as suitable couplingreagents, or for example carbonyldiimidazole,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, anddicyclohexyl-carbodiimide, optionally in the presence of a catalyst suchas dimethylaminopyridine or 4-pyrrolidinopyridine, optionally in thepresence of a base for example N-methyl-morpholine, triethylamine,pyridine, or 2,6-di-alkyl-pyridines such as 2,6-lutidine or2,6-di-tert-butylpyridine. Suitable solvents include dimethylacetamide,dichloromethane, benzene, tetrahydrofuran and dimethylformamide. Thecoupling reaction may conveniently be performed at a temperature in therange of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for exampleacid chlorides, and active esters, for example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Compounds of formula (III) may be prepared according to Scheme 1:

wherein PG is a nitrogen protecting group such as those defined hereinbelow; and L is a displaceable group such as those defined herein above.

Compounds of formula (II) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process b) Compounds of formula (IV) and (V) in a suitable solvent suchas dimethylformamide, N-methylpyrrolidine, or N-methyl 2-pyrrolidinoneand optionally in the presence of a base such as triethylamine ordiisopropylethylamine are heated together at a temperature range between50 to 100° C.

Compounds of formula (IV) may be prepared according to Scheme 2:

wherein PG is a nitrogen protecting group such as those defined hereinbelow. Compounds of formula (IV) may also be prepared from a carboxylicacid derivative (IVd) and an amine derivative (IVb) using standardpeptide coupling reagents as described hereinabove (see Scheme 3).

Compounds of formula (V) may be prepared according to Scheme 4:

Wherein FGI is functional group interconversion of the NH₂ group to therequired “L”. For example, a compound of formula (Vd) in glacial aceticacid and concentrated HCl can be treated with sodium nitrite to convertthe amino group to a chloro group.Process c) Compounds of formula (VI) and (VII) in a suitable solventsuch as methanol, ethanol, or tetrahydrofuran in the presence of a basesuch as sodium hydroxide, lithium hydroxide, or barium hydroxide arereacted at a temperature range of 25 to 100° C.

Compounds of formula (VI) may be prepared by a suitable modification ofthe reactions described herein to make a compound of formula (I) whereinR⁴ is hydrogen.

Compounds of formula (VII) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

Process d) Suitable deprotection conditions are described hereinbelow.

Compounds of formula (VIII) may be prepared by a suitable modificationof the reactions described herein to make a compound of formula (I).

The formation of a pharmaceutically-acceptable salt is within the skillof an ordinary organic chemist using standard techniques.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. The reagents used to introduce such ringsubstituents are either commercially available or are made by processesknown in the art.

Introduction of substituents into a ring may convert one compound of theformula (I) into another compound of the formula (I). Such reactions andmodifications include, for example, introduction of a substituent bymeans of an aromatic substitution reaction, reduction of substituents,alkylation of substituents, oxidation of substituents, esterification ofsubstituents, amidation of substituents, formation of heteroaryl rings.The reagents and reaction conditions for such procedures are well knownin the chemical art. Particular examples of aromatic substitutionreactions include the introduction of alkoxides, diazotization reactionsfollowed by introduction of thiol group, alcohol group, halogen group.Examples of modifications include; oxidation of alkylthio toalkylsulphinyl or alkylsulphonyl.

The skilled organic chemist will be able to use and adapt theinformation contained and referenced within the above references, andaccompanying Examples therein and also the Examples herein, to obtainnecessary starting materials, and products. If not commerciallyavailable, the necessary starting materials for the procedures such asthose described above may be made by procedures which are selected fromstandard organic chemical techniques, techniques which are analogous tothe synthesis of known, structurally similar compounds, or techniqueswhich are analogous to the above described procedure or the proceduresdescribed in the examples. It is noted that many of the startingmaterials for synthetic methods as described above are commerciallyavailable and/or widely reported in the scientific literature, or couldbe made from commercially available compounds using adaptations ofprocesses reported in the scientific literature. The reader is furtherreferred to Advanced Organic Chemistry, 4^(th) Edition, by Jerry March,published by John Wiley & Sons 1992, for general guidance on reactionconditions and reagents.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups incompounds. The instances where protection is necessary or desirable areknown to those skilled in the art, as are suitable methods for suchprotection. Conventional protecting groups may be used in accordancewith standard practice (for illustration see T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, 1991).

Examples of a suitable protecting group for a hydroxy group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, anaroyl group, for example benzoyl, a silyl group such as trimethylsilylor an arylmethyl group, for example benzyl. The deprotection conditionsfor the above protecting groups will necessarily vary with the choice ofprotecting group. Thus, for example, an acyl group such as an alkanoylor an aroyl group may be removed, for example, by hydrolysis with asuitable base such as an alkali metal hydroxide, for example lithium orsodium hydroxide. Alternatively a silyl group such as trimethylsilyl maybe removed, for example, by fluoride or by aqueous acid; or anarylmethyl group such as a benzyl group may be removed, for example, byhydrogenation in the presence of a catalyst such as palladium-on-carbon.

A suitable protecting group for an amino group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an alkoxycarbonylgroup, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonylgroup, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, oran aroyl group, for example benzoyl. The deprotection conditions for theabove protecting groups necessarily vary with the choice of protectinggroup. Thus, for example, an acyl group such as an alkanoyl oralkoxycarbonyl group or an aroyl group may be removed for example, byhydrolysis with a suitable base such as an alkali metal hydroxide, forexample lithium or sodium hydroxide. Alternatively an acyl group such asa t-butoxycarbonyl group may be removed, for example, by treatment witha suitable acid as hydrochloric, sulphuric or phosphoric acid ortrifluoroacetic acid and an arylmethoxycarbonyl group such as abenzyloxycarbonyl group may be removed, for example, by hydrogenationover a catalyst such as palladium-on-carbon, or by treatment with aLewis acid for example boron tris(trifluoroacetate). A suitablealternative protecting group for a primary amino group is, for example,a phthaloyl group which may be removed by treatment with an alkylamine,for example dimethylaminopropylamine or 2-hydroxyethylamine, or withhydrazine.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or for example, an allyl group which may beremoved, for example, by use of a palladium catalyst such as palladiumacetate.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art,or they may be removed during a later reaction step or work-up.

Optically active forms of a compound of the invention may be obtained bycarrying out one of the above procedures using an optically activestarting material (formed, for example, by asymmetric induction of asuitable reaction step), or by resolution of a racemic form of thecompound or intermediate using a standard procedure, or bychromatographic separation of diastereoisomers (when produced).Enzymatic techniques may also be useful for the preparation of opticallyactive compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the invention isrequired, it may be obtained by carrying out one of the above proceduresusing a pure regioisomer as a starting material, or by resolution of amixture of the regioisomers or intermediates using a standard procedure.

Enzyme Potency Testing Methods

E. coli GyrB ATPase Inhibition Activity: Compounds can be tested forinhibition of E. coli GyrB ATPase activity using an ammoniummolybdate/malachite green-based phosphate detection assay (Lanzetta, P.A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).Assays can be performed in multiwell plates in 30 μl reactionscontaining 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mMmagnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol,1 mM 1,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.6 μg/mlsheared salmon sperm DNA, 400 pM E. coli GyrA, 400 pM E. coli GyrB, 250μM ATP, and compound in dimethylsulfoxide. Reactions can be quenchedwith 30 μl of ammonium molybdate/malachite green detection reagentcontaining 1.2 mM malachite green hydrochloride, 8.5 mM ammoniummolybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read inan absorbance plate reader at 650 nm and percent inhibition values arecalculated using dimethylsulfoxide (2%)-containing reactions as 0%inhibition and EDTA-containing (2.4 μM) reactions as 100% inhibitioncontrols. An IC₅₀ measurement of compound potency for each compound canbe determined from reactions performed in the presence of 10 differentcompound concentrations.E. coli Topoisomerase IV ATPase Inhibition Activity: Compounds can betested for inhibition of E. coli topoisomerase IV ATPase activity asdescribed above for E. coli GyrB except the 30 μl reactions containedthe following: 20 mM TRIS buffer pH 8, 50 mM ammonium acetate, 8 mMmagnesium chloride, 5% glycerol, 5 mM 1,4-Dithio-DL-threitol, 0.005%Brij-35, 5 μg/ml sheared salmon sperm DNA, 500 pM E. coli ParC, 500 pME. coli ParE, 160 μM ATP, and compound in dimethylsulfoxide. An IC₅₀measurement of compound potency for each compound can be determined fromreactions performed in the presence of 10 different compoundconcentrations.S. aureus GyrB ATPase Inhibition Activity: Compounds may be tested forinhibition of S. aureus GyrB ATPase activity using an ammoniummolybdate/malachite green-based phosphate detection assay (Lanzetta, P.A., L. J. Alvarez, P. S. Reinach, and O. A. Candia, 1979, 100: 95-97).Assays can be performed in multiwell plates in 30 μl reactionscontaining 50 mM Hepes buffer pH 7.5, 75 mM ammonium acetate, 8.0 mMmagnesium chloride, 0.5 mM ethylenediaminetetraacetic acid, 5% glycerol,1.0 mM 1,4-Dithio-DL-threitol, 200 nM bovine serum albumin, 1.0 μg/mlsheared salmon sperm DNA, 250 pM E. coli GyrA, 250 pM S. aureus GyrB,250 μM ATP, and compound in dimethylsulfoxide. Reactions can be quenchedwith 30 μl of ammonium molybdate/malachite green detection reagentcontaining 1.2 mM malachite green hydrochloride, 8.5 mM ammoniummolybdate tetrahydrate, and 1 M hydrochloric acid. Plates can be read inan absorbance plate reader at 650 nm and percent inhibition values canbe calculated using dimethylsulfoxide (2%)-containing reactions as 0%inhibition and EDTA-containing (2.4 μM) reactions as 100% inhibitioncontrols. An IC₅₀ measurement of compound potency for each compound canbe determined from reactions performed in the presence of 10 differentcompound concentrations.

Compounds of the invention were tested in an assay substantially similarto the assay described above for measuring the inhibition of S. aureusGyrB ATPase. Percent inhibition of S. aureus GyrB ATPase at a compoundconcentration of 1 μM (unless otherwise noted) is disclosed in thefollowing table:

% Inhibition at Example # 1 μM 1 99 2 103 4 97 5 5 6 99 7 100 8 100 9 9810 90 11 101 12 106 13 99 14 91 15 98 16 103 17 106 18 108 19 112 20 11821 118 22 112 23 100 24 120 25 119 26 97 27 102 28 98 29 98 61 105 62 9863 104 64 104 65 107 86 105 87 109 88 107 89 110 90 103 91 105 92 102 9394 94 104 95 114 96 104 97 112 98 116 99 106 100 102 101 117 102 112 103102 104 105 124 112 125 111 126 108 127 110 128 110 129 103 130 107 131108 132 103 133 112 134 104 135 98 136 104 137 101 138 103 139 99 140107 141 103 142 103 164 117 165 107 166 110 167 113 168 102 169 102 170119 171 101 172 109 173 104 174 102 175 106 176 108 177 107 178 102 179104 180 103 181 101 182 117 183 116 189 106 190 100 191 102 192 108 193109 195 118 200 106 201 105 202 103 203 108 208 108 209 105 210 109 211107 215 106 216 109 217 113

Bacterial Susceptibility Testing Methods

Compounds may be tested for antimicrobial activity by susceptibilitytesting in liquid media. Compounds may be dissolved in dimethylsulfoxideand tested in 10 doubling dilutions in the susceptibility assays. Theorganisms used in the assay may be grown overnight on suitable agarmedia and then suspended in a liquid medium appropriate for the growthof the organism. The suspension can be a 0.5 McFarland and a further 1in 10 dilution can be made into the same liquid medium to prepare thefinal organism suspension in 100 μL. Plates can be incubated underappropriate conditions at 37° C. for 24 hrs prior to reading. TheMinimum Inhibitory Concentration (MIC) may be determined as the lowestdrug concentration able to reduce growth by 80% or more.

In an assay comparable to the above, Example 23 had an MIC of 0.78 μg/mlagainst Streptococcus pneumoniae.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically-acceptable saltthereof for use in a method of treatment of the human or animal body bytherapy.

We have found that compounds of the present invention inhibit bacterialDNA gyrase and/or topoisomerase IV and are therefore of interest fortheir antibacterial effects. In one aspect of the invention thecompounds of the invention inhibit bacterial DNA gyrase and aretherefore of interest for their antibacterial effects. In one aspect ofthe invention, the compounds of the invention inhibit topoisomerase IVand are therefore of interest for their antibacterial effects. In oneaspect of the invention, the compounds of the invention inhibit both DNAgyrase and topoisomerase IV and are therefore of interest for theirantibacterial effects.

It is expected that the compounds of the present invention will beuseful in treating bacterial infections. In one aspect of the invention“infection” or “bacterial infection” refers to a gynecologicalinfection. In one aspect of the invention “infection” or “bacterialinfection” refers to a respiratory tract infection (RTI). In one aspectof the invention “infection” or “bacterial infection” refers to asexually transmitted disease. In one aspect of the invention “infection”or “bacterial infection” refers to a urinary tract infection. In oneaspect of the invention “infection” or “bacterial infection” refers toacute exacerbation of chronic bronchitis (ACEB). In one aspect of theinvention “infection” or “bacterial infection” refers to acute otitismedia. In one aspect of the invention “infection” or “bacterialinfection” refers to acute sinusitis. In one aspect of the invention“infection” or “bacterial infection” refers to an infection caused bydrug resistant bacteria. In one aspect of the invention “infection” or“bacterial infection” refers to catheter-related sepsis. In one aspectof the invention “infection” or “bacterial infection” refers tochancroid. In one aspect of the invention “infection” or “bacterialinfection” refers to chlamydia. In one aspect of the invention“infection” or “bacterial infection” refers to community-acquiredpneumoniae (CAP). In one aspect of the invention “infection” or“bacterial infection” refers to complicated skin and skin structureinfection. In one aspect of the invention “infection” or “bacterialinfection” refers to uncomplicated skin and skin structure infection. Inone aspect of the invention “infection” or “bacterial infection” refersto endocarditis. In one aspect of the invention “infection” or“bacterial infection” refers to febrile neutropenia. In one aspect ofthe invention “infection” or “bacterial infection” refers to gonococcalcervicitis. In one aspect of the invention “infection” or “bacterialinfection” refers to gonococcal urethritis. In one aspect of theinvention “infection” or “bacterial infection” refers tohospital-acquired pneumonia (HAP). In one aspect of the invention“infection” or “bacterial infection” refers to osteomyelitis. In oneaspect of the invention “infection” or “bacterial infection” refers tosepsis. In one aspect of the invention “infection” or “bacterialinfection” refers to syphilis.

In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Acinetobacter baumanii. In one aspectof the invention an “infection” or “bacterial infection” refers to aninfection caused by Acinetobacter haemolyticus. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Acinetobacter junii. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byAcinetobacter johnsonii. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused by Acinetobacterlwoffi. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Bacteroides bivius. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Bacteroides fragilis. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Burkholderia cepacia. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byCampylobacter jejuni. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Chlamydiapneumoniae. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Chlamydia urealyticus. Inone aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Chlamydophila pneumoniae. In one aspectof the invention an “infection” or “bacterial infection” refers to aninfection caused by Clostridium difficili. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Enterobacter aerogenes. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byEnterobacter cloacae. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Enterococcusfaecalis. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Enterococcus faecium. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Escherichia coli. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Gardnerella vaginalis. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byHaemophilus parainfluenzae. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byHaemophilus influenzae. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Helicobacterpylori. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Klebsiella pneumoniae. Inone aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Legionella pneumophila. In one aspectof the invention an “infection” or “bacterial infection” refers to aninfection caused by Methicillin-resistant Staphylococcus aureus. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Methicillin-susceptible Staphylococcus aureus.In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Moraxella catarrhalis. In one aspect ofthe invention an “infection” or “bacterial infection” refers to aninfection caused by Morganella morganii. In one aspect of the inventionan “infection” or “bacterial infection” refers to an infection caused byMycoplasma pneumoniae. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Neisseriagonorrhoeae. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Penicillin-resistantStreptococcus pneumoniae. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused byPenicillin-susceptible Streptococcus pneumoniae. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Peptostreptococcus magnus. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byPeptostreptococcus micros. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused byPeptostreptococcus anaerobius. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byPeptostreptococcus asaccharolyticus. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byPeptostreptococcus prevotii. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byPeptostreptococcus tetradius. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byPeptostreptococcus vaginalis. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byProteus mirabilis. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Pseudomonasaeruginosa. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Quinolone-ResistantStaphylococcus aureus. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused byQuinolone-Resistant Staphylococcus epidermis. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Salmonella typhi. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused bySalmonella paratyphi. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Salmonellaenteritidis. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Salmonella typhimurium. Inone aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Serratia marcescens. In one aspect ofthe invention an “infection” or “bacterial infection” refers to aninfection caused by Staphylococcus aureus. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Staphylococcus epidermidis. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byStaphylococcus saprophyticus. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byStreptoccocus agalactiae. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused by Streptococcusagalactiae. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Streptococcus pneumoniae. Inone aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Streptococcus pyogenes. In one aspectof the invention an “infection” or “bacterial infection” refers to aninfection caused by Stenotrophomonas maltophilia. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Ureaplasma urealyticum. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byVancomycin-Resistant Enterococcus faecium. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Vancomycin-Resistant Enterococcus faecalis. In one aspect ofthe invention an “infection” or “bacterial infection” refers to aninfection caused by Vancomycin-Resistant Staphylococcus aureus. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Vancomycin-Resistant Staphylococcus epidermis.

In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Acinetobacter spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Bacteroides spp. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused by Burkholderiaspp. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Campylobacter spp. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Chlamydia spp. In one aspect of the inventionan “infection” or “bacterial infection” refers to an infection caused byChlamydophila spp. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Clostridium spp.In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Enterobacter spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Enterococcus spp. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byEscherichia spp. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Gardnerella spp.In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Haemophilus spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Helicobacter spp. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused byKlebsiella spp. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Legionella spp.In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Moraxella spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Morganella spp. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused by Mycoplasmaspp. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Neisseria spp. In one aspectof the invention an “infection” or “bacterial infection” refers to aninfection caused by Peptostreptococcus spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Proteus spp. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Pseudomonas spp.In one aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by Salmonella spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Serratia spp. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by Staphylococcusspp. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by Streptoccocus spp. In oneaspect of the invention an “infection” or “bacterial infection” refersto an infection caused by Stenotrophomonas spp. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by Ureaplasma spp. In one aspect of the invention an “infection”or “bacterial infection” refers to an infection caused by aerobes. Inone aspect of the invention an “infection” or “bacterial infection”refers to an infection caused by obligate anaerobes. In one aspect ofthe invention an “infection” or “bacterial infection” refers to aninfection caused by facultative anaerobes. In one aspect of theinvention an “infection” or “bacterial infection” refers to an infectioncaused by gram-positive bacteria. In one aspect of the invention an“infection” or “bacterial infection” refers to an infection caused bygram-negative bacteria. In one aspect of the invention an “infection” or“bacterial infection” refers to an infection caused by gram-variablebacteria. In one aspect of the invention an “infection” or “bacterialinfection” refers to an infection caused by atypical respiratorypathogens.

According to a further feature of the present invention there isprovided a method for producing an antibacterial effect in a warmblooded animal, such as man, in need of such treatment, which comprisesadministering to said animal an effective amount of a compound of thepresent invention, or a pharmaceutically-acceptable salt thereof.

According to a further feature of the invention there is provided amethod for inhibition of bacterial DNA gyrase and/or topoisomerase IV ina warm-blooded animal, such as a human being, in need of such treatmentwhich comprises administering to said animal an effective amount of acompound of formula (I), or a pharmaceutically acceptable salt thereofas defined hereinbefore.

According to a further feature of the invention there is provided amethod of treating a bacterial infection in a warm-blooded animal, suchas a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof as definedhereinbefore.

According to a further feature of the invention there is provided amethod of preventing a bacterial infection in a warm-blooded animal,such as a human being, in need of such treatment which comprisesadministering to said animal an effective amount of a compound offormula (I), or a pharmaceutically acceptable salt thereof as definedhereinbefore.

According to a further feature of the invention there is provided amethod of treating a bacterial infection selected from a gynecologicalinfection, a respiratory tract infection (RTI), a sexually transmitteddisease, a urinary tract infection, acute exacerbation of chronicbronchitis (ACEB), acute otitis media, acute sinusitis, an infectioncaused by drug resistant bacteria, catheter-related sepsis, chancroid,chlamydia, community-acquired pneumoniae (CAP), complicated skin andskin structure infection, uncomplicated skin and skin structureinfection, endocarditis, febrile neutropenia, gonococcal cervicitis,gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis,sepsis and/or syphilis in a warm-blooded animal, such as a human being,in need of such treatment which comprises administering to said animalan effective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

According to a further feature of the invention there is provided amethod of preventing a bacterial infection selected from a gynecologicalinfection, a respiratory tract infection (RTI), a sexually transmitteddisease, a urinary tract infection, acute exacerbation of chronicbronchitis (ACEB), acute otitis media, acute sinusitis, an infectioncaused by drug resistant bacteria, catheter-related sepsis, chancroid,chlamydia, community-acquired pneumoniae (CAP), complicated skin andskin structure infection, uncomplicated skin and skin structureinfection, endocarditis, febrile neutropenia, gonococcal cervicitis,gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis,sepsis and/or syphilis in a warm-blooded animal, such as a human being,in need of such treatment which comprises administering to said animalan effective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt thereof as defined hereinbefore.

A further feature of the present invention is a compound of formula (I),and pharmaceutically acceptable salts thereof for use as a medicament.Suitably the medicament is an antibacterial agent.

According to a further aspect of the invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for the production of ananti-bacterial effect in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for the inhibition ofbacterial DNA gyrase and/or topoisomerase IV in a warm-blooded animalsuch as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment of abacterial infection in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the prevention of abacterial infection in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the treatment of abacterial infection selected from a gynecological infection, arespiratory tract infection (RTI), a sexually transmitted disease, aurinary tract infection, acute exacerbation of chronic bronchitis(ACEB), acute otitis media, acute sinusitis, an infection caused by drugresistant bacteria, catheter-related sepsis, chancroid, chlamydia,community-acquired pneumoniae (CAP), complicated skin and skin structureinfection, uncomplicated skin and skin structure infection,endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcalurethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsisand/or syphilis in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is providedthe use of a compound of formula (I), or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the prevention of abacterial infection selected from a gynecological infection, arespiratory tract infection (RTI), a sexually transmitted disease, aurinary tract infection, acute exacerbation of chronic bronchitis(ACEB), acute otitis media, acute sinusitis, an infection caused by drugresistant bacteria, catheter-related sepsis, chancroid, chlamydia,community-acquired pneumoniae (CAP), complicated skin and skin structureinfection, uncomplicated skin and skin structure infection,endocarditis, febrile neutropenia, gonococcal cervicitis, gonococcalurethritis, hospital-acquired pneumonia (HAP), osteomyelitis, sepsisand/or syphilis in a warm-blooded animal such as a human being.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in the production of an anti-bacterial effect in a warm-bloodedanimal such as a human being.

According to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in inhibition of bacterial DNA gyrase and/or topoisomerase IV ina warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in the treatment of a bacterial infection in a warm-bloodedanimal such as a human being.

Thus according to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in the prevention of a bacterial infection in a warm-bloodedanimal such as a human being.

Thus according to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in the treatment of a bacterial infection selected from agynecological infection, a respiratory tract infection (RTI), a sexuallytransmitted disease, a urinary tract infection, acute exacerbation ofchronic bronchitis (ACEB), acute otitis media, acute sinusitis, aninfection caused by drug resistant bacteria, catheter-related sepsis,chancroid, chlamydia, community-acquired pneumoniae (CAP), complicatedskin and skin structure infection, uncomplicated skin and skin structureinfection, endocarditis, febrile neutropenia, gonococcal cervicitis,gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis,sepsis and/or syphilis in a warm-blooded animal such as a human being.

Thus according to a further aspect of the invention there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in the prevention of a bacterial infection selected from agynecological infection, a respiratory tract infection (RTI), a sexuallytransmitted disease, a urinary tract infection, acute exacerbation ofchronic bronchitis (ACEB), acute otitis media, acute sinusitis, aninfection caused by drug resistant bacteria, catheter-related sepsis,chancroid, chlamydia, community-acquired pneumoniae (CAP), complicatedskin and skin structure infection, uncomplicated skin and skin structureinfection, endocarditis, febrile neutropenia, gonococcal cervicitis,gonococcal urethritis, hospital-acquired pneumonia (HAP), osteomyelitis,sepsis and/or syphilis in a warm-blooded animal such as a human being.

In order to use a compound of the formula (I), or apharmaceutically-acceptable salt thereof, for the therapeutic (includingprophylactic) treatment of mammals including humans, in particular intreating infection, it is normally formulated in accordance withstandard pharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula(I), or a pharmaceutically-acceptable salt thereof, and apharmaceutically-acceptable diluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), asdefined hereinbefore or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier foruse in producing an anti-bacterial effect in a warm-blooded animal, suchas a human being.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), asdefined hereinbefore, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier foruse in inhibition of bacterial DNA gyrase and/or topoisomerase IV in awarm-blooded animal, such as a human being.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), asdefined hereinbefore, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier foruse in the treatment of a bacterial infection in a warm-blooded animal,such as a human being.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), asdefined hereinbefore, or a pharmaceutically acceptable salt thereof, inassociation with a pharmaceutically acceptable excipient or carrier foruse in the treatment of a gynecological infection, a respiratory tractinfection (RTI), a sexually transmitted disease, a urinary tractinfection, acute exacerbation of chronic bronchitis (ACEB), acute otitismedia, acute sinusitis, an infection caused by drug resistant bacteria,catheter-related sepsis, chancroid, chlamydia, community-acquiredpneumoniae (CAP), complicated skin and skin structure infection,uncomplicated skin and skin structure infection, endocarditis, febrileneutropenia, gonococcal cervicitis, gonococcal urethritis,hospital-acquired pneumonia (HAP), osteomyelitis, sepsis and/or syphilisin a warm-blooded animal, such as a human being.

The compositions of the invention may be in a form suitable for oral use(for example as tablets, lozenges, hard or soft capsules, aqueous oroily suspensions, emulsions, dispersible powders or granules, syrups orelixirs), for topical use (for example as creams, ointments, gels, oraqueous or oily solutions or suspensions), for administration byinhalation (for example as a finely divided powder or a liquid aerosol),for administration by insufflation (for example as a finely dividedpowder) or for parenteral administration (for example as a sterileaqueous or oily solution for intravenous, subcutaneous, intramuscular orintramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventionalprocedures using conventional pharmaceutical excipients, well known inthe art. Thus, compositions intended for oral use may contain, forexample, one or more colouring, sweetening, flavouring and/orpreservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid; binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate, andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case, using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxycetanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),colouring agents, flavouring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavouring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavouring and colouringagents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, an esters or partial esters derived from fatty acids andhexitol anhydrides (for example sorbitan monooleate) and condensationproducts of the said partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavouring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavouring and/or colouring agent.

The pharmaceutical compositions may also be in the form of a sterileinjectable aqueous or oily suspension, which may be formulated accordingto known procedures using one or more of the appropriate dispersing orwetting agents and suspending agents, which have been mentioned above. Asterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally-acceptable diluent or solvent,for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of aconventional pressurised aerosol arranged to dispense the activeingredient either as an aerosol containing finely divided solid orliquid droplets. Conventional aerosol propellants such as volatilefluorinated hydrocarbons or hydrocarbons may be used and the aerosoldevice is conveniently arranged to dispense a metered quantity of activeingredient.

For further information on formulation the reader is referred to Chapter25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch;Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or moreexcipients to produce a single dosage form will necessarily varydepending upon the host treated and the particular route ofadministration. For example, a formulation intended for oraladministration to humans will generally contain, for example, from 0.5mg to 2 g of active agent compounded with an appropriate and convenientamount of excipients which may vary from about 5 to about 98 percent byweight of the total composition. Dosage unit forms will generallycontain about 1 mg to about 500 mg of an active ingredient. For furtherinformation on Routes of Administration and Dosage Regimes the reader isreferred to Chapter 25.3 in Volume 5 of Comprehensive MedicinalChemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press1990.

The compounds of the invention described herein may be applied as a soletherapy or may involve, in addition to a compound of the invention, oneor more other substances and/or treatments. Such conjoint treatment maybe achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination. Suitable classes and substances may be selected fromone or more of the following:

i) other antibacterial agents for example macrolides e.g. erythromycin,azithromycin or clarithromycin; quinolones e.g. ciprofloxacin orlevofloxacin; β-lactams e.g. penicillins e.g. amoxicillin orpiperacillin; cephalosporins e.g. ceftriaxone or ceftazidime;carbapenems, e.g. meropenem or imipenem etc; aminoglycosides e.g.gentamicin or tobramycin; or oxazolidinones; and/or

ii) anti-infective agents for example, an antifungal triazole e.g. oramphotericin; and/or

iii) biological protein therapeutics for example antibodies, cytokines,bactericidal/permeability-increasing protein (BPI) products; and/or

iv) efflux pump inhibitors.

Therefore, in a further aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable saltthereof, and a chemotherapeutic agent selected from:

i) one or more additional antibacterial agents; and/or

ii) one or more anti-infective agents; and/or

iii) biological protein therapeutics for example antibodies, cytokines,bactericidal/permeability-increasing protein (BPI) products; and/or

iv) one or more efflux pump inhibitors.

In another embodiment, the invention relates to a method of treating abacterial infection in an animal, such as a human, comprisingadministering to the animal an effective amount of a compound of formula(I), or a pharmaceutically acceptable salt thereof, and achemotherapeutic agent selected from:

i) one or more additional antibacterial agents; and/or

ii) one or more anti-infective agents; and/or

iii) biological protein therapeutics for example antibodies, cytokines,bactericidal/permeability-increasing protein (BPI) products; and/or

iv) one or more efflux pump inhibitors.

As stated above the size of the dose required for the therapeutic orprophylactic treatment of a particular disease state will necessarily bevaried depending on the host treated, the route of administration, theseverity of the illness being treated, and whether or not an additionalchemotherapeutic agent is administered in combination with a compound ofthe invention. Preferably a daily dose in the range of 1-50 mg/kg isemployed. However the daily dose will necessarily be varied dependingupon the host treated, the particular route of administration, theseverity of the illness being treated, and whether or not an additionalchemotherapeutic agent is administered in combination with a compound ofthe invention. Accordingly the optimum dosage may be determined by thepractitioner who is treating any particular patient.

As noted above, one embodiment of the present invention is directed totreating or preventing diseases caused by bacterial infections, whereinthe bacteria comprise a GyrB ATPase or topoisomerase IV ATPase enzyme.Treating a subject with a bacterial infection includes achieving,partially or substantially, one or more of the following: the reducingor amelioration of the progression, severity and/or duration of theinfection, arresting the spread of an infection, ameliorating orimproving a clinical symptom or indicator associated with a theinfection (such as tissue or serum components), and preventing thereoccurrence of the infection.

As used herein, the terms “preventing a bacterial infection” refer tothe reduction in the risk of acquiring the infection, or the reductionor inhibition of the recurrence of the infection. In a preferredembodiment, a compound of the invention is administered as apreventative measure to a patient, preferably a human, before a surgicalprocedure is preformed on the patient to prevent infection.

As used herein, the term “effective amount” refers to an amount of acompound of this invention for treating or preventing a bacterialinfection is an amount which is sufficient to prevent the onset of aninfection, reduce or ameliorate the severity, duration, or progression,of an infection, prevent the advancement of an infection, cause theregression of an infection, prevent the recurrence, development, onsetor progression of a symptom associated with an infection, or enhance orimprove the prophylactic or therapeutic effect(s) of another therapy.

In addition to its use in therapeutic medicine, compounds of formula(I), and their pharmaceutically acceptable salts are also useful aspharmacological tools in the development and standardisation of in-vitroand in-vivo test systems for the evaluation of the effects of inhibitorsof DNA gyrase and/or topoisomerase IV in laboratory animals such ascats, dogs, rabbits, monkeys, rats and mice, as part of the search fornew therapeutic agents.

In the above other, pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and particularembodiments of the compounds of the invention described herein alsoapply.

Combinations

The compounds of the invention described herein may be applied as a soletherapy or may involve, in addition to a compound of the invention, oneor more other substances and/or treatments. Such conjoint treatment maybe achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Where theadministration is sequential or separate, the delay in administering thesecond component should not be such as to lose the beneficial effect ofthe combination. Suitable classes and substances may be selected fromone or more of the following:

i) other antibacterial agents for example macrolides e.g. erythromycin,azithromycin or clarithromycin; quinolones e.g. ciprofloxacin orlevofloxacin; β-lactams e.g. penicillins e.g. amoxicillin orpiperacillin; cephalosporins e.g. ceftriaxone or ceftazidime;carbapenems, e.g. meropenem or imipenem etc; aminoglycosides e.g.gentamicin or tobramycin; or oxazolidinones; and/orii) anti-infective agents for example, an antifungal triazole e.g. oramphotericin; and/oriii) biological protein therapeutics for example antibodies, cytokines,bactericidal/permeability-increasing protein (BPI) products; and/oriv) efflux pump inhibitors.

Therefore, in a further aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable saltthereof and a chemotherapeutic agent selected from:

i) one or more additional antibacterial agents; and/orii) one or more anti-infective agents; and/oriii) biological protein therapeutics for example antibodies, cytokines,bactericidal/permeability-increasing protein (BPI) products; and/oriv) one or more efflux pump inhibitors.

EXAMPLES

The invention is now illustrated but not limited by the followingExamples in which unless otherwise stated:—

(i) evaporations were carried out by rotary evaporation in-vacuo andwork-up procedures were carried out after removal of residual solids byfiltration;(ii) operations were generally carried out at ambient temperature, thatis typically in the range 18-26° C. and without exclusion of air unlessotherwise stated, or unless the skilled person would otherwise workunder an inert atmosphere;(iii) column chromatography (by the flash procedure) was used to purifycompounds and was performed on Merck Kieselgel silica (Art. 9385) unlessotherwise stated;(iv) yields are given for illustration only and are not necessarily themaximum attainable;(v) the structure of the end-products of the invention were generallyconfirmed by NMR and mass spectral techniques; proton magnetic resonancespectra is quoted and was generally determined in DMSO-d₆ unlessotherwise stated using a Bruker DRX-300 spectrometer operating at afield strength of 300 MHz. Chemical shifts are reported in parts permillion downfield from tetramethysilane as an internal standard (δscale) and peak multiplicities are shown thus: s, singlet; d, doublet;AB or dd, doublet of doublets; dt, doublet of triplets; dm, doublet ofmultiplets; t, triplet, m, multiplet; br, broad;(vi) fast-atom bombardment (FAB) mass spectral data were generallyobtained using a Platform spectrometer (supplied by Micromass) run inelectrospray and, where appropriate, either positive ion data ornegative ion data were collected or using Agilent 1100series LC/MSDequipped with Sedex 75ELSD, run in atmospheric pressure chemicalionisation mode and, where appropriate, either positive ion data ornegative ion data were collected; mass spectra were run with an electronenergy of 70 electron volts in the chemical ionization (CI) mode using adirect exposure probe; where indicated ionization was effected byelectron impact (EI), fast atom bombardment (FAB) or electrospray (ES);values for m/z are given; generally, only ions which indicate the parentmass are reported;(vii) each intermediate was generally purified to the standard requiredfor the subsequent stage and was characterised in sufficient detail toconfirm that the assigned structure was correct; purity was assessed byhigh pressure liquid chromatography, thin layer chromatography, or NMRand identity was determined by infra-red spectroscopy (IR), massspectroscopy or NMR spectroscopy as appropriate;(vii) the following abbreviations may be used:

CDCl₃ is deuterated chloroform;

DCM is dichloromethane;

DIEA is diisopropyl ethyl amine;

DMF is N,N-dimethylformamide;

DMSO is dimethylsulfoxide;

dppf is 1,1′-bis(diphenylphosphino)ferrocene;

EDC is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide;

EtOAc is ethyl acetate;

EtOH is ethanol;

HATU isN-[(dimethylamino)-1H,2,3-triazolo[4,5-b-]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide;

HOBt is 1-hydroxybenzotriazole;

MeOH is methanol;

MS is mass spectroscopy;

Pd₂(dba)₃ is tris(dibenzylideneacetone)dipalladium(0));

SM is starting material;

TFA is trifluoroacetic acid;

THF is tetrahydrofuran; and

(viii) temperatures are quoted as ° C.

Example 12-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy(piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid

A solution of methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate(Example 30, 90 mg, 0.162 mmol) and 2N sodium hydroxide (4 mL) inmethanol (30 mL) was stirred at room temperature for 4 h. The reactionmixture was concentrated under reduced pressure and the resultingresidue was dissolved in water, which was acidified to pH 3 with 2 Nhydrochloric acid (2 mL). The resulting solid was collected byfiltration and dried to afford2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid (40 mg, 72%) as solid.

LCMS: m/z 540.1 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.80 (m, 2H), 2.18 (s, 3H), 3.42 (m, 1H),3.67 (s, 3H), 3.96 (m, 2H), 4.18 (m, 1H), 4.31 (m, 2H), 5.11 (d, 1H),5.22 (d, 1H), 5.84 (m, 1H), 7.12 (d, 1H), 8.00 (s, 1H), 12.14 (s, 1H).

Examples 2-30

The following Examples were prepared by the procedure described inExample 1 from the starting materials (SM) indicated.

Ex Compound Data SM 2

¹H NMR (400 MHz, DMSO- d₆): δ 1.75 (m, 2H), 2.18 (s, 3H), 2.87 (m, 2H),3.08 (m, 2H), 3.93 (m, 1H), 4.19 (q, 2H), 5.19 (d, 1H), 5.34 (d, 1H),5.89 (m, 1H), 7.13 (d, 1H), 12.12 (s, 1H). Example 31 3

¹H NMR (400 MHz, DMSO- d₆): δ 1.80 (m, 2H), 2.18 (s, 3H), 3.71 (m, 4H),4.00 (t, 2H), 4.18 (m, 1H), 4.27 (d, 1H), 5.16 (d, 1H), 5.23 (d, 1H),5.82 (m, 1H), 7.13 (d, 1H), 7.56 (m, 1H), 7.78 (t, 1H), 8.45 (d, 1H),12.15 (s, 1H). Example 32 4

¹H NMR (400 MHz, DMSO- d₆): δ 1.80 (m, 2H), 2.18 (s, 3H), 3.29 (m, 1H),3.65 (s, 1H), 4.00 (t, 2H), 4.22 (m, 3H), 5.09 (d, 1H), 5.21 (d, 1H),5.80 (m, 1H), 7.16 (d, 1H), 8.64 (d, 2H), 8.81 (s, 1H), 12.13 (s, 1H).Example 33 5

¹H NMR (400 MHz, DMSO- d₆): δ 1.73 (m, 1H), 1.92 (m, 1H), 2.21 (s, 3H),4.04 (m, 5H), 4.26 (m, 2H), 5.06 (d, 1H), 5.17 (d, 1H), 5.84 (m, 1H),7.79 (d, 1H), 8.25 (s, 1H), 12.80 (s, 1H). Example 34 6

¹H NMR (400 MHz, DMSO- d₆): δ 1.70 (m, 2H), 2.10 (s, 3H), 3.65 (br s,2H), 3.97 (m, 4H), 4.30 (br s, 2H), 5.04 (d, 1H), 5.17 (d, 1H), 5.80 (m,1H), 7.41 (d, 1H), 7.62 (m, 2H), 8.38 (d, 1H). Example 35 7

¹H NMR (400 MHz, DMSO- d₆): δ 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (s, 3H),3.44 (m, 2H), 4.02 (m, 3H), 4.28 (m, 2H), 5.04 (d, 1H), 5.15 (d, 1H),5.81 (m, 1H), 7.72 (d, 1H), 8.83 (d, 2H), 9.35 (s, 1H), 12.71 (s, 1H).¹H NMR (400 MHz, DMSO-d₆): δ 1.73 (m, 1H), 1.90 (m, 1H), 2.20 (s, 3H),3.44 (m, 2H), 4.02 (m, 3H), 4.28 (m, 2H), 5.04 (d, 1H), 5.15 (d, 1H),5.81 (m, 1H), 7.72 (d, 1H), 8.83 (d, 2H), 9.35 (s, 1H), 12.71 (s, 1H).Example 36 8

LCMS: m/z 528 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.08 (t, 3H), 1.78(m, 2H), 2.18 (s, 3H), 3.32 (m, 2H), 3.42 (m, 3H), 3.65 (s, 3H), 3.69(s, 3H), 4.00 (m, 1H), 7.18 (d, 1H), 8.00 (s, 1H), 12.15 (s, 1H).Example 37 9

LCMS: m/z 571 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.08 (t, 3H), 1.81(m, 2H), 2.18 (s, 3H), 3.17 (s, 3H), 3.40 (t, 2H), 3.45 (m, 2H), 3.50(t, 4H), 4.28 (m, 2H), 6.95 (s, 1H), 7.15 (d, 1H), 7.25 (s, 1H), 12.18(s, 1H). Example 38 10

LCMS: m/z 542 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.07 (m, 3H), 1.78(m, 2H), 2.18 (s, 3H), 3.40 (m, 3H), 3.71 (m, 3H), 4.02 (m, 3H), 4.31(m, 1H), 7.18 (d, 1H), 7.56 (d, 1H), 7.89 (t, 1H), 8.45 (d, 1H). Example39 11

LCMS: m/z 525 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.09 (t, 3H), 1.79(m, 2H), 2.18 (s, 3H), 3.42 (m, 3H), 3.66 (s, 1H), 3.68 (m, 2H), 4.09(m, 1H), 4.28 (m, 2H), 7.14 (d, 1H), 8.70 (d, 2H), 8.82 (s, 1H), 12.15(s, 1H). Example 40 12

LCMS: m/z 519.1 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H),1.73 (m, 1H), 1.83 (m, 1H), 2.18 (s, 3H), 3.42 (m, 4H), 3.63 (s, 3H),4.00 (m, 2H), 4.24 (m, 2H), 7.57 (d, 1H), 7.98 (s, 1H), 12.66 (s, 1H)Example 41 13

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (t, 3H), 1.81 (m, 2H), 2.20 (s, 3H),3.17 (s, 3H), 3.51 (m, 4H), 3.61 (s, 3H), 4.01 (m, 2H), 4.45 (m, 2H),6.94 (s, 1H), 7.25 (s, 1H), 7.58 (d, 1H), 12.69 (s, 1H). Example 42 14

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (m, 3H), 1.74 (m, 2H), 2.20 (s, 3H),3.39 (m, 3H), 3.63 (m, 2H), 4.01 (m, 2H), 4.17 (m, 1H), 7.56 (m, 2H),7.78 (t, 1H), 8.45 (d, 1H), 12.68 (s, 1H). Example 43 15

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (m, 3H), 1.81 (m, 2H), 2.20 (s, 3H),3.41 (m, 3H), 3.75 (m, 3H), 4.18 (m, 2H), 4.25 (m, 1H), 8.65 (d, 2H),8.81 (s, 1H), 12.13 (s, 1H). Example 44 16

LCMS: m/z 494.2 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 1.03 (t, 3H),1.64 (d, 1H), 1.97 (m, 1H), 2.16 (s, 3H), 3.42 (m, 2H), 3.56 (m, 1H),3.65 (m, 1H), 3.68 (m, 1H), 3.73 (s, 3H), 4.21 (m, 3H), 6.88 (s, 1H),7.63 (d, 1H), 8.00 (s, 1H), 11.60 (s, 1H). Example 45 17

LCMS: m/z 508.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (m, 3H),1.61 (d, 1H), 1.89 (m, 1H), 2.16 (s, 3H), 3.41 (m, 3H), 3.59 (m, 1H),3.68 (s, 1H), 4.02 (m, 2H), 4.20 (m, 1H), 6.84 (s, 1H), 7.56 (m, 1H),7.62 (d, 1H), 7.80 (t, 1H), 8.47 (d, 1H), 11.60 (s, 1H). Example 46 18

LCMS: m/z 491.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (m, 3H),1.61 (d, 1H), 1.91 (m, 1H), 2.16 (s, 3H), 3.41 (m, 2H), 3.58 (m, 1H),3.67 (m, 1H), 4.08 (m, 3H), 4.21 (m, 1H), 6.86 (s, 1H), 7.60 (d, 1H),8.68 (d, 2H), 8.82 (s, 1H), 11.60 (s, 1H). Example 47 19

LCMS: m/z 464.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.87 (d, 3H),1.84 (m, 2H), 2.17 (s, 3H), 3.65 (m, 5H), 3.83 (m, 2H), 4.08 (s, 3H),4.27 (m, 1H), 6.91 (s, 1H), 7.68 (d, 1H), 8.24 (s, 1H), 11.67 (s, 1H).Example 48 20

LCMS: m/z 478.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.87 (d, 3H),1.80 (m, 2H), 2.14 (s, 3H), 3.49 (m, 3H), 3.77 (br s, 1H), 4.24 (s, 1H),6.93 (s, 1H), 7.55 (d, 1H), 7.59 (d, 1H), 7.79 (m, 1H), 8.46 (s, 1H),11.60 (s, 1H). Example 49 21

LCMS: m/z 461.2 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.87 (d, 3H),1.78 (m, 2H), 2.12 (s, 3H), 3.58 (m, 3H), 3.86 (br s, 1H), 4.28 (s, 1H),6.91 (s, 1H), 7.62 (d, 1H), 8.76 (d, 2H), 9.27 (s, 1H), 11.62 (s, 1H).Example 50 22

LCMS: m/z 498.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.93 (d, 3H),1.82 (br s, 2H), 2.17 (s, 3H), 3.63 (m, 6H), 4.05 (s, 3H), 4.25 (br s,1H), 7.21 (d, 1H), 8.22 (s, 1H), 12.05 (s, 1H). Example 51 23

LCMS: m/z 541.3 (M + H); ¹H NMR (400 MHz, DMSO- d₆): 0.95 (d, 3H), 1.90(br s, 3H), 2.19 (s, 3H), 3.24 (s, 3H), 3.62 (m, 4H), 3.71 (t, 3H), 4.39(br s, 1H), 4.82 (br s, 2H), 7.21 (d, 1H), 7.34 (s, 1H), 7.51 (s, 1H),12.02 (s, 1H). Example 52 24

LCMS: m/z 512.26 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.93 (d, 3H),1.88 (br s, 2H), 2.16 (s, 3H), 3.57 (m, 5H), 4.22 (s, 1H), 7.47 (s, 2H),7.71 (d, 1H), 8.40 (s, 1H). Example 53 25

LCMS: m/z 495.1 (M + H); ¹H NMR (400 MHz, DMSO- d₆): δ 0.94 (d, 3H),1.82 (br s, 2H), 2.17 (s, 3H), 3.78 (m, 5H), 4.25 (br s, 1H), 7.24 (brs, 1H), 8.81 (d, 2H), 9.32 (s, 1H), 11.60 (s, 1H). Example 54 26

LCMS: m/z 489.3 (M + H); ¹H NMR (DMSO-d₆, 400 MHz): δ 0.95 (d, 3H), 1.84(br s, 2H), 2.21 (s, 4H), 3.69 (m, 5H), 4.06 (s, 3H), 4.28 (br s, 1H),7.98 (d, 1H), 8.23 (s, 1H), 12.60 (s, 1H). Example 55 27

LCMS: m/z 532.21 (M + H); ¹H NMR (DMSO-d₆, 400 MHz): δ 0.92 (d, 3H),1.80 (br s, 2H), 1.88 (s, 1H), 2.14 (s, 3H), 3.23 (s, 3H), 3.55 (br s,3H), 3.70 (br s, 3H), 4.26 (br s, 1H), 4.73 (br s, 2H), 7.28 (s, 1H),7.47 (s, 1H), 7.88 (br s, 1H). Example 56 28

LCMS: m/z 503.3 (M + H); ¹H NMR (DMSO-d₆, 400 MHz): δ 0.92 (d, 3H), 1.80(br s, 2H), 2.20 (s, 4H), 3.46 (m, 1H), 3.74 (m, 4H), 4.24 (s, 1H), 7.51(s, 1H), 7.73 (br s, 1H), 7.98 (br s, 1H), 8.44 (s, 1H), 12.77 (br s,1H). Example 57 29

LCMS: m/z 486.3 (M + H); ¹H NMR (DMSO-d₆, 400 MHz): δ 0.92 (d, 3H), 2.21(s, 4H), 3.64 (m, 3H), 3.66 (s, 1H), 4.25 (br s, 1H), 7.94 (d, 1H), 8.76(s, 1H), 8.81 (s, 1H), 9.31 (s, 1H), 12.61 (s, 1H), 15.18 (br s, 1H).Example 58

Example 30 Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazole-5-yl)-1,3-thiazole-5-carboxylate

Methyl2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate(Intermediate 2, 77.91 mg, 3.02 mmol) was added to a solution of3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide(Intermediate 20, 100 mg, 3.02 mmol) and N,N-diisopropylethylamine(0.362 mL, 0.06 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and theresulting reaction mixture was stirred overnight at 80° C. The reactionmixture was cooled to room temperature and poured into water (20 mL).The solid that formed was collected by filtration, washed withdiethylether (25 mL) and dried to afford Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate(90 mg, 70%) as solid.

LCMS: m/z 553 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.80 (m, 2H), 2.18 (s, 3H), 3.42 (m, 1H),3.67 (s, 3H), 3.72 (s, 3H), 3.96 (m, 2H), 4.18 (m, 1H), 4.31 (m, 2H),5.11 (d, 1H), 5.22 (d, 1H), 5.84 (m, 1H), 7.12 (d, 1H), 8.00 (s, 1H),12.14 (s, 1H).

Examples 31-58

The following Examples were prepared by the procedure described inExample 30 from the starting materials (SM) indicated.

Ex Compound Data SM 31

LCMS: m/z 596 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.75 (m, 2H), 2.18(s, 3H), 2.87 (m, 2H), 3.08 (d, 2H), 3.66 (s, 3H), 3.93 (m, 1H), 4.19(q, 2H), 5.19 (d, 1H), 5.34 (d, 1H), 5.89 (m, 1H), 7.13 (d, 1H), 12.12(s, 1H). Intermediate 20 and Intermediate 1 32

LCMS: m/z 581 (M + H); NMR (400 MHz, DMSO-d₆): δ 1.02 (t, 3H), 1.80 (m,2H), 2.18 (s, 3H), 3.71 (m, 4H), 4.00 (m, 2H), 4.02 (q, 2H), 4.18 (m,1H), 4.27 (d, 1H), 5.16 (d, 1H), 5.23 (d, 1H), 5.82 (m, 1H), 7.13 (d,1H), 7.56 (m, 1H), 7.78 (t, 1H), 8.45 (d, 1H), 12.15 (s, 1H).Intermediate 20 and Intermediate 4 33

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (t, 3H), 1.80 (m, 2H), 2.18 (s, 3H),3.29 (m, 1H), 3.65 (s, 1H), 4.00 (m, 2H), 4.04 (q, 2H), 4.22 (m, 3H),5.09 (d, 1H), 5.21 (d, 1H), 5.80 (m, 1H), 7.16 (d, 1H), 8.64 (d, 2H),8.81 (s, 1H), 12.13 (s, 1H). Intermediate 20 and Intermediate 3 34

¹H NMR (400 MHz, DMSO- d₆) δ 1.74 (m, 1H), 1.90 (m, 1H), 2.19 (s, 3H),3.42 (m, 2H), 3.74 (s, 7H), 4.02 (m, 3H), 4.26 (br s, 2H), 5.08 (d, 1H),5.24 (d, 1H), 5.85 (m, 1H), 7.67 (d, 1H), 8.01 (s, 1H), 12.67 (s, 1H).Intermediate 22 and Intermediate 2 35

LCMS: m/z 573 (M + H). ¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H), 1.73(m, 1H), 1.90 (m, 1H), 2.20 (s, 3H), 3.41 (m, 2H), 3.73 (br s, 2H), 4.05(m, 5H), 4.25 (m, 2H), 5.08 (d, 1H), 5.23 (d, 1H), 5.85 (m, 1H), 7.55(m, 1H), 7.70 (d, 1H), 7.71 (t, 1H), 8.46 (d, 1H). Intermediate 22 andIntermediate 4 36

LCMS: m/z 556 (M + H). ¹H NMR (400 MHz, DMSO- d₆): 1.07 (t, 3H), 1.72(m, 1H), 1.88 (m, 1H), 2.19 (s, 3H), 3.41 (m, 2H), 3.73 (br s, 1H), 4.09(m, 5H), 4.26 (m, 2H), 5.08 (d, 1H), 5.22 (d, 1H), 5.85 (m, 1H), 7.68(d, 1H), 8.70 (d, 2H), 8.83 (s, 1H), 12.70 (s, 1H). Intermediate 22 andIntermediate 3 37

¹H NMR (400 MHz, DMSO- d₆): δ 1.08 (t, 3H), 1.78 (m, 2H), 2.18 (s, 3H),3.32 (m, 2H), 3.42 (m, 3H), 3.65 (s, 3H), 3.69 (s, 3H), 4.00 (m, 1H),4.26 (d, 2H), 7.18 (d, 1H), 8.00 (s, 1H), 12.15 (s, 1H). Intermediate 26and Intermediate 2 38

¹H NMR (400 MHz, DMSO- d₆): δ 1.08 (t, 3H), 1.81 (m, 2H), 2.18 (s, 3H),3.17 (s, 3H), 3.40 (m, 2H), 3.45 (m, 2H), 3.50 (m, 4H), 3.61 (s, 3H),3.68 (m, 2H), 4.28 (m, 2H), 6.95 (s, 1H), 7.15 (d, 1H), 7.25 (s, 1H),12.18 (s, 1H). Intermediate 26 and Intermediate 1 39

¹H NMR (400 MHz, DMSO- d₆): δ 1.07 (m, 6H), 1.78 (m, 2H), 2.18 (s, 3H),3.40 (m, 3H), 3.71 (m, 3H), 4.02 (m, 3H), 4.31 (m, 2H), 7.18 (d, 1H),7.56 (d, 1H), 7.89 (m, 1H), 8.45 (d, 1H). Intermediate 26 andIntermediate 4 40

¹H NMR (400 MHz, DMSO- d₆): δ 0.95 (t, 3H), 1.09 (t, 3H), 1.79 (m, 2H),2.18 (s, 3H), 3.42 (m, 3H), 3.66 (s, 1H), 3.68 (m, 2H), 4.09 (m, 2H),4.28 (m, 2H), 7.14 (d, 1H), 8.70 (d, 2H), 8.82 (s, 1H), 12.15 (s, 1H).Intermediate 26 and Intermediate 3 41

¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H), 1.73 (m, 1H), 1.83 (m, 1H),2.18 (s, 3H), 3.42 (m, 4H), 3.63 (s, 3H), 3.70 (s, 3H), 4.00 (m, 2H),4.24 (m, 2H), 7.57 (d, 1H), 7.98 (s, 1H), 12.66 (s, 1H). Intermediate 33and Intermediate 2 42

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (t, 3H), 1.81 (m, 2H), 2.20 (s, 3H),3.17 (s, 3H), 3.51 (m, 4H), 3.61 (s, 3H), 3.68 (m, 3H), 4.01 (m, 2H),4.45 (m, 2H), 6.94 (s, 1H), 7.25 (s, 1H), 7.58 (d, 1H), 12.69 (s, 1H).Intermediate 33 and Intermediate 1 43

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (m, 6H), 1.74 (m, 2H), 2.20 (s, 3H),3.39 (m, 3H), 3.63 (m, 2H), 4.01 (m, 2H), 4.17 (m, 3H), 7.56 (m, 2H),7.78 (t, 1H), 8.45 (d, 1H), 12.68 (s, 1H). Intermediate 33 andIntermediate 4 44

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (m, 6H), 1.81 (m, 2H), 2.20 (s, 3H),3.41 (m, 3H), 3.75 (m, 3H), 4.18 (m, 4H), 4.25 (m, 1H), 8.65 (d, 2H),8.81 (s, 1H), 12.13 (s, 1H). Intermediate 33 and Intermediate 3 45

¹H NMR (400 MHz, DMSO- d₆): δ 1.03 (t, 3H), 1.64 (d, 1H), 1.97 (m, 1H),2.16 (s, 3H), 3.42 (m, 2H), 3.56 (m, 1H), 3.65 (m, 4H), 3.68 (m, 1H),3.73 (s, 3H), 4.21 (m, 3H), 6.88 (s, 1H), 7.63 (d, 1H), 8.00 (s, 1H),11.60 (s, 1H). Intermediate 35 and Intermediate 2 46

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (m, 6H), 1.61 (d, 1H), 1.89 (m, 1H),2.16 (s, 3H), 3.41 (m, 3H), 3.59 (m, 1H), 3.68 (s, 1H), 4.02 (m, 4H),4.20 (m, 1H), 6.84 (s, 1H), 7.56 (m, 1H), 7.62 (d, 1H), 7.80 (t, 1H),8.47 (d, 1H), 11.60 (s, 1H). Intermediate 35 and Intermediate 4 47

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (m, 6H), 1.61 (d, 1H), 1.91 (m, 1H),2.16 (s, 3H), 3.41 (m, 2H), 3.58 (m, 3.67 (m, 1H), 4.08 (m, 5H), 4.21(m, 1H), 6.86 (s, 1H), 7.60 (d, 1H), 8.68 (d, 2H), 8.82 (s, 1H), 11.60(s, 1H). Intermediate 35 and Intermediate 3 48

¹H NMR (400 MHz, DMSO- d₆): δ 0.92 (d, 3H), 1.80 (m, 2H), 2.19 (s, 3H),2.69 (s, 1H), 3.53 (br s, 1H), 3.58 (m, 3H), 3.65 (s, 3H), 3.72 (s, 3H),3.78 (m, 1H), 4.25 (br s, 1H), 6.92 (s, 1H), 7.59 (d, 1H), 8.00 (s, 1H).Intermediate 39 and Intermediate 2 49

¹H NMR (400 MHz, DMSO- d₆): δ 0.92 (d, 3H), 1.05 (t, 3H), 1.74 (m, 2H),2.14 (s, 3H), 3.56 (m, 4H), 3.57 (br s, 1H), 4.02 (q, 2H), 4.25 (br s,1H), 6.93 (s, 1H), 7.58 (m, 2H), 7.78 (m, 1H), 8.46 (d, 1H), 11.59 (s,1H). Intermediate 39 and Intermediate 4 50

¹H NMR (400 MHz, DMSO- d₆): δ 0.86 (d, 3H), 1.16 (d, 3H), 1.72 (m, 2H),2.17 (s, 3H), 3.56 (m, 3H), 3.82 (br s, 1H), 4.18 (q, 2H), 4.24 (m, 1H),6.91 (s, 1H), 7.58 (d, 1H), 8.81 (s, 1H), 11.58 (s, 1H). Intermediate 39and Intermediate 3 51

¹H NMR (400 MHz, DMSO- d₆): δ 0.94 (d, 3H), 1.83 (br s, 2H), 2.19 (s,3H), 3.51 (m, 1H), 3.58 (m, 1H), 3.65 (s, 3H), 3.67 (s, 3H), 4.26 (br s,1H), 7.18 (d, 1H), 8.00 (s, 1H), 12.01 (s, 1H). Intermediate 41 andIntermediate 2 52

¹H NMR (400 MHz, DMSO- d₆): δ 0.95 (d, 3H), 1.85 (br s, 2H), 2.21 (s,4H), 3.21 (s, 3H), 3.54 (d, 4H), 3.63 (d, 4H), 3.63 (s, 4H), 3.71 (m,1H), 4.04 (q, 2H), 4.28 (br s, 1H), 6.92 (s, 1H), 7.21 (d, 1H), 7.28 (s,1H), 12.01 (s, 1H). Intermediate 41 and Intermediate 1 53

¹H NMR (400 MHz, DMSO- d₆): δ 0.93 (d, 3H), 1.05 (t, 3H), 1.82 (br s,2H), 2.19 (s, 3H), 3.65 (m, 4H), 4.06 (q, 2H), 4.23 (br s, 1H), 7.19 (d,1H), 7.57 (m, 1H), 7.78 (m, 1H), 8.46 (s, 1H), 12.01 (s, 1H).Intermediate 41 and Intermediate 4 54

¹H NMR (400 MHz, DMSO- d₆): δ 0.93 (d, 3H), 1.17 (t, 3H), 1.85 (br s,2H), 2.20 (s, 3H), 3.49 (m, 5H), 4.25 (br s, 1H), 8.67 (d, 2H), 8.76 (d,1H), 8.82 (s, 1H). Intermediate 41 and Intermediate 3 55

¹H NMR (DMSO-d₆, 400 MHz): δ 0.94 (d, 3H), 1.83 (br s, 2H), 2.21 (s,3H), 2.18 (br s, 1H), 3.30 (m, 3H), 3.65 (s, 3H), 3.72 (s, 3H), 4.51 (brs, 1H), 7.94 (d, 1H), 8.01 (s, 1H), 12.61 (s, 1H). Intermediate 43 andIntermediate 2 56

¹H NMR (DMSO-d₆, 400 MHz): δ 0.94 (d, 3H), 1.81 (br s, 2H), 2.21 (s,4H), 3.21 (s, 3H), 3.51 (t, 3H), 3.62 (s, 4H), 3.72 (m, 1H), 4.03 (q,2H), 4.26 (br s, 1H), 6.98 (s, 1H), 7.23 (s, 1H), 7.84 (d, 1H), 12.61(s, 1H). Intermediate 43 and Intermediate 1 57

¹H NMR (DMSO-d₆, 400 MHz): δ 0.94 (s, 3H), 1.03 (t, 3H), 1.82 (s, 2H),2.17 (s, 1H), 3.67 (m, 4H), 4.06 (q, 2H), 4.24 (br s, 1H), 7.56 (s, 1H),7.78 (m, 1H), 7.90 (s, 1H), 8.47 (s, 1H), 12.56 (s, 1H). Intermediate 43and Intermediate 4 58

¹H NMR (DMSO-d₆, 400 MHz): δ 0.94 (d, 3H), 1.19 (t, 3H), 1.84 (s, 2H),2.19 (br s, 1H), 2.21 (s, 3H), 3.63 (m, 5H), 4.08 (q, 2H), 4.24 (s, 1H),7.92 (d, 1H), 8.66 (d, 2H), 8.83 (s, 1H), 12.56 (s, 1H). Intermediate 43and Intermediate 3

Example 59 Ethyl4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate

Ethyl 2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate(Intermediate 47, 120 mg, 0.3960 mM) was added to a solution of3,4-dichloro-N-[(3R,4S)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide(WO2006087543, 127 mg, 0.4158 mM) and N,N-diisopropylethylamine (159.6mg, 1.247 mM) in N-methyl 2-pyrrolidinone (1.0 mL) and the resultingreaction mixture was stirred at 50-55° C. for 1 h. The reaction mixturewas cooled to room temperature and then poured into water (40 mL). Theresulting solid was collected by filtration and dried to afford ethyl4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate140 mg (90%) of as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.12 (t, 2H), 1.78 (m, 2H), 2.21 (s, 3H),3.22-3.60 (m, 7H), 4.12 (q, 2H), 4.36 (d, 2H), 7.18 (d, 1H), 8.78 (s,1H), 8.87 (s, 1H), 12.18 (s, 1H).

MASS (APCI) m/z 573.0 (M+H)

Example 60 Ethyl2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate

Ethyl4-(5-chloropyrazin-2-yl)-2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate(Example 59, 100 mg, 0.1748 mM) was added to a solution of1-methylpiperazine (87.93 mg, 0.874 mM) and N,N-diisopropylethylamine(67.12 mg, 0.5244 mM) in N-methyl 2-pyrrolidinone (1.5 mL) and theresulting reaction mixture was stirred for over night at 80-90° C. Aftercompletion of the reaction, the reaction mixture was poured into water(40 mL), and the obtained solid was filtered and dried to afford ethyl2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate92 mg (82%) as off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.12 (t, 2H), 1.78 (m, 2H), 2.20 (s, 3H),2.21 (s, 3H), 2.41 (m, 4H), 3.22-3.60 (m, 7H), 3.64 (m, 4H), 4.12 (q,2H), 4.36 (d, 2H), 7.18 (d, 1H), 8.37 (s, 2H), 12.18 (s, 1H).

MASS (APCI) m/z 637 (M+H)

Example 612-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylicacid

Ethyl2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate(Example 60, 92 mg, 0.144 mM) was dissolved in methanol (15 mL). To thiswas added 2N sodium hydroxide (7 mL) and the reaction mixture wasstirred at room temperature for 4 h. The methanol was completelyevaporated and water (20 mL) was added. The aqueous layer was washedwith diethyl ether (2×20 mL) and the aqueous layer was acidified to pH 6with 2N hydrochloric acid (1.0 mL). The solid that precipitated out ofsolution was filtered and dried to afford2-[(3R,4S)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylicacid 60 mg (82%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.75 (s, 2H), 1.87 (m, 2H), 2.18 (s, 3H),2.22 (s, 3H), 2.41 (m, 4H), 3.26-3.53 (m, 5H), 3.62 (m, 4H), 3.88 (br s,1H), 4.24 (br s, 1H), 7.25 (d, 1H), 8.31 (s, 1H), 8.73 (s, 1H).

LC_MS: m/z 609.4 (M+H)

Example 622-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylicacid

To a stirred solution of 2-(pyrrolidine-1-yl)ethanol (0.102 mL, 0.872mmol) in dry tetrahydrofuran (20 mL) was added sodium hydride (70 mg,1.771 mmol) at 0° C. The reaction mixture was heated to 80° C. After 10min, ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate(Example 59, 250 mg, 0.436 mmol) was added to the reaction mixture at80° C. and further maintained at 80° C. for 10 min. After the completionof the reaction, the reaction mixture was cooled and carefully quenchedby adding ice pieces. The aqueous layer was extracted with ethyl acetate(2×50 mL) to get rid of any organic impurities and discarded. Theaqueous layer was acidified to pH=2 using 2N HCl solution and wasextracted with 10% methanol/dichloromethane (2×100 mL). The organiclayer was dried and concentrated under reduced pressure to yield theproduct. The obtained product was stirred in acetonitrile (10 mL). Thesolid was filtered and dried to obtain 120 mg (45%) of2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-{5-[2-(pyrrolidin-1-yl)ethoxy]pyrazin-2-yl}-1,3-thiazole-5-carboxylicacid as yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.72-1.77 (m, 6H), 2.18 (s, 3H), 2.65 (m,4H), 2.96 (m, 3H), 3.34-3.39 (m, 5H), 3.57 (t, 1H), 4.00 (m, 1H),4.27-4.29 (m, 1H), 4.50-4.53 (m, 3H), 7.16-7.18 (d, 1H), 8.46 (s, 1H),8.94 (s, 1H), 12.17 (s, 1H).

LC-MS: m/z 623 (M+H).

Examples 63-65

The following Examples were prepared according to the proceduredescribed for Example 62 from the starting materials given in the Table.

Ex Compound Data SM 63

¹H NMR (400 MHz, DMSO- d₆): δ 1.78 (m, 2H), 2.18 (s, 3H), 2.24 (s, 6H),2.71-2.82 (m, 2H), 3.27-3.31 (m, 2H), 3.38 (s, 4H), 3.57 (m, 1H), 3.98(m, 1H), 4.27-4.60 (m, 4H), 7.16-7.18 (d, 1H), 8.46 (s, 1H), 8.95 (s,1H), 12.17 (s, 1H). LC-MS: m/z 598 (M + H) Example 59 and N,N-dimethyl-aminoethanol 64

¹H NMR (400 MHz, DMSO- d₆): δ 1.78 (m, 2H), 2.16 (s, 3H), 2.18 (s, 3H),2.33 (m, 4H), 2.71-2.82 (m, 2H), 3.31- 3.36 (m, 5H), 3.34-3.38 (m, 2H),3.388 (s, 3H), 3.57 (t, 1H), 3.98 (m, 1H), 4.27-4.29 (m, 1H), 4.49-4.51(m, 3H), 7.15-7.17 (d, 1H), 8.45 (s, 1H), 8.95 (s, 1H), 12.14 (s, 1H).LC-MS: m/z 652 (M + H). Example 59 and N- methylpiperazine ethanol 65

¹H NMR (400 MHz, DMSO- d₆): δ 1.23-1.25 (m, 3H), 1.35 (m, 2H), 1.62-1.77(m, 6H), 2.18 (s, 3H), 2.53 (s, 3H), 2.71-2.82 (m, 2H), 3.13-3.16 (m,1H), 3.34-3.38 (m, 2H), 3.388 (s, 3H), 3.57 (t, 1H), 3.98 (m, 1H),4.27-4.29 (m, 1H), 4.43-4.46 (m, 3H), 7.17- 7.19 (d, 1H), 8.44 (s, 1H),8.94 (s, 1H), 12.18 (s, 1H). LC-MS: m/z 651 (M + H). Example 59 and N-methylpiperdine4- ethanol

Example 66

Ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate

To the stirred the solution of3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide(Intermediate 26, 650 mg, 2.03 mmol) and ethyl2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate(Intermediate 47, 636 mg, 1.828 mmol) in N-methylpyrrolidine was addedN,N-diisopropyl ethylamine and stirred at stirred at 60° C. for 3 h. Thereaction mixture was cooled to room temperature and poured on to icewater. The precipitate was collected by filtration and dried to afford950 mg (79%) of ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate.

¹H NMR (400 MHz, CDCl₃): δ 1.21-1.31 (m, 6H), 1.95-2.11 (m, 2H), 2.31(s, 3H), 3.21 (m, 2H), 3.41 (m, 4H), 3.80 (m, 1H), 4.20 (m, 2H), 4.31(m, 1H), 4.41 (m, 1H), 8.65 (m, 2H), 9.01 (s, 1H).

LC-MS: m/z 587 (M+H).

Example 67 Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate

To a stirred solution of ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate(Example 66, 120 mg, 0.204 mmol) and piperidine (87 mg 1.023 mmol) inN-methyl pyrrolidine was added N,N-diisopropyl ethylamine; the reactionmixture was then stirred over night at 80° C. The reaction mixture wascooled to room temperature and poured on to ice cold water. Theprecipitated product was collected by filtration and dried to afford 120mg (92%) of ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate.

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.23 (t, 3H), 1.75 (m, 6H),2.02 (m, 2H), 2.32 (s, 3H), 3.21 (m, 2H), 3.42 (m, 2H), 3.61 (m, 5H),4.21 (m, 5H), 4.42 (m, 1H), 8.17 (s, 1H), 8.45 (s, 1H), 9.29 (m, 1H).

LC-MS: m/z 636.47 (M+H).

Examples 68-85

The following Examples were prepared according to the procedure forExample 67 from the starting materials indicated in the table.

Ex Compound Data SM 68

¹H NMR (400 MHz, CDCl₃): δ 1.21 (t, 3H), 1.27 (t, 3H), 2.08 (m, 2H),2.27 (s, 3H), 3.22 (m, 2H), 3.43 (m, 2H), 3.63 (m, 5H), 3.83 (m, 4H),4.22 (m, 4H), 4.4 (m, 1H), 7.28 (d, 1H), 8.17 (s, 1H), 8.49 (s, 1H),9.52 (m, 1H). LC-MS: m/z 638.55 (M + H) Example 66 and morpholine 69

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.23 (t, 3H), 2.05 (m, 2H),2.35 (2s, 6H), 2.53 (m, 4H), 3.42 (m, 2H), 3.60 (m, 5H), 3.8 (m, 2H),4.21 (m, 4H), 4.42 (m, 1H), 7.28 (d, 1H), 8.18 (s, 1H), 8.47 (s, 1H),9.49 (m, 1H). LC-MS: m/z 651.59 (M + H) Example 66 and N-methylpiperazine 70

¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, 3H), 1.18 (t, 3H), 2.03 (m, 2H),2.27 (s, 3H), 3.02 (m, 4H), 3.22 (m, 2H), 3.41 (m, 2H), 3.62 (m, 5H),4.21 (m, 4H), 4.42 (m, 1H), 8.18 (s, 1H), 8.47 (s, 1H), 9.18 (m, 1H)LC-MS: m/z 637.60 (M + H) Example 66 and piperazine 71

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.23 (t, 3H), 2.02 (m, 2H),2.35 (s, 3H), 3.22 (m, 2H), 3.41 (s, 3H), 3.42 (m, 2H), 3.61 (m, 5H),4.21 (m, 4H), 4.21 (m, 1H), 5.05 (m, 1H), 7.25 (d, 1H), 7.97 (s, 1H),8.40 (s, 1H), 9.19 (m, 1H). LC-MS: m/z (M + H) Example 66 and 2-methoxy-ethylamine 72

¹H NMR (400 MHz, CDCl₃): δ 0.88 (t, 3H), 1.15 (t, 3H), 2.02 (m, 2H),2.29 (s, 3H), 2.55 (m, 4H), 2.62 (m, 2H), 3.21 (m, 2H), 3.42 (m, 4H),3.62 (m, 1H), 3.75 (m, 6H), 4.20 (m, 2H), 4.31 (m, 1H), 5.39 (m, 1H),7.98 (s, 1H), 8.41 (s, 1H), 9.34 (s, 1H). LC-MS: m/z 681 (M + H) Example66 and 4- morpholino- ethylamien 73

¹H NMR (400 MHz, CDCl₃): δ 0.88 (t, 3H), 1.16 (t, 3H), 2.05 (m, 2H),2.31 (s, 3H), 3.42 (m, 13H), 4.31 (2s, 6H), 4.41 (m, 1H), 7.26 (d, 1H),7.97 (s, 1H), 8.40 (s, 1H), 9.52 (m, 1H). LC-MS: m/z 670.67 (M + H).Example 66 and 1,3- dimethoxyprpane- 2-yl-amine 74

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (t, 3H), 1.07 (t, 3H), 1.77 (m, 2H),2.18 (s, 3H), 3.21 (m, 4H), 3.37 (m, 6H), 3.64 (m, 1H), 3.71 (m, 2H),4.11 (m, 3H), 4.23 (m, 2H), 6.31 (s, 1H), 7.15 (d, 1H), 7.41 (m, 1H),7.93 (s, 1H), 8.21 (s, 1H), 12.17 (s, 1H). LC-MS: m/z 680.43 (M + H)Example 66 and 2- oxoimidazolidin-1- yl)ethylamine 75

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.21 (t, 3H), 2.03 (m, 2H),2.25 (m, 9H), 2.59 (m, 2H), 3.21 (m, 2H), 3.42 (m, 4H), 3.61 (m, 1H),4.22 (m, 4H), 4.41 (m, 1H), 5.54 (m, 1H), 7.98 (s, 1H), 8.40 (s, 1H),9.33 (s, 1H). LC-MS: m/z 639.43 (M + H) Example 66 and dimethylamino-ethylamine 76

¹H NMR (400 MHz, CDCl₃): δ 1.26 (t, 3H), 1.34 (m, 3H), 1.95 (m, 2H),2.07 (m, 2H), 2.32 (s, 3H), 2.41 (s, 3H), 2.73 (m, 8H), 3.23 (m, 2H),3.48 (m, 4H), 3.82 (m, 1H), 4.23 (m, 4H), 4.42 (m, 1H), 8.02 (s, 1H),8.21 (s, 1H), 9.13 (s, 1H). LC-MS: m/z 694 (M + H) Example 66 and 4-methylpiperazin-1- yl-ethylamine 77

¹H NMR (400 MHz, CDCl₃): δ 0.95 (m, 6H), 1.23 (t, 3H), 1.34 (t, 3H),1.35 (m, 1H), 2.01 (m, 2H), 2.22 (d, 2H), 2.35 (s, 3H), 2.53 (m, 4H),3.24 (m, 2H), 3.46 (m, 2H), 3.63 (m, 4H), 4.21 (m, 2H), 4.43 (m, 2H),4.56 (m, 1H), 7.22 (d, 1H), 8.23 (s, 1H), 8.44 (s, 1H), 9.4 (s, 1H).LC-MS: m/z 693 (M + H) Example 66 and 4-(2- methylpropyl)piper- azine 78

¹H NMR (400 MHz, CDCl₃): δ 0.89 (t, 3H), 1.18 (t, 3H), 1.92 (m, 6H),2.01 (m, 2H), 2.21 (m, 1H), 2.35 (m, 6H), 2.42 (m, 2H), 2.61(m, 2H),2.95 (m, 2H), 3.05 (m, 2H), 3.21 (m, 2H), 3.41 (m, 2H), 3.62 (m, 4H),4.15 (m, 1H), 4.21 (m, 2H), 4.31 (m, 2H), 4.41 (m, 1H), 8.17 (s, 1H),8.46 (s, 1H), 9.41 (s, 1H). LC-MS: m/z 748.57 (M + H) Example 66 and4-(1- methylpiperidin- 3-yl)methylpiper- azine 79

¹H NMR (400 MHz, CDCl₃): δ 1.22 (m, 3H), 1.33 (m, 3H), 1.35 (m, 2H),1.82 (m, 12H), 2.03 (m, 1H), 2.25 (d, 2H), 2.36 (s, 3H), 2.54 (m, 4H),3.21 (m, 2H), 3.45 (m, 1H), 3.62 (m, 4H), 4.22 (m, 4H), 4.41 (m, 1H),8.25 (s, 1H), 8.44 (s, 1H), 9.42 (s, 1H). LC-MS: m/z 734 (M + H) Example66 and cyclohexyl- methylpiperazine 80

¹H NMR (400 MHz, CDCl₃): δ 0.91 (m, 6H), 1.22 (t, 3H), 1.31 (m, 4H),1.51 (m, 3H), 2.02 (m, 2H), 2.22 (m, 1H), 2.25 (s, 3H), 2.64 (m, 4H),3.23 (m, 2H), 3.46 (m, 2H), 3.61 (m, 4H), 4.10 (m, 1H), 4.22 (m, 2H),4.31 (m, 2H), 4.45 (m, 1H), 8.22 (s, 1H), 8.45 (s, 1H), 9.42 (s, 1H).LC-MS: m/z 708 (M + H) Example 66 and 1-(1- ethylpropyl)piper- azine 81

¹H NMR (400 MHz, CDCl₃): δ 1.22 (m, 5H), 1.35 (m, 6H), 2.01 (m, 2H),2.32 (s, 3H), 2.65 (m, 4H), 3.25 (m, 2H), 3.41 (m, 1H), 3.85 (m, 6H),4.24 (m, 4H), 4.42 (m, 1H), 8.26 (s, 1H), 8.45 (s, 1H), 9.25 (s, 1H).LC-MS: m/z 665.4 (M + H) Example 66 and ethylpiperazine 82

¹H NMR (400 MHz, CDCl₃): δ 1.22 (m, 6H), 1.32 (m, 6H), 1.92 (m, 2H),2.15 (m, 2H), 2.34 (s, 3H), 2.62 (m, 10H), 3.21 (m, 2H), 3.44 (m, 1H),3.62 (m, 4H), 3.81 (m, 2H), 4.22 (m, 4H), 4.41 (m, 1H), 8.22 (s, 1H),8.41 (s, 1H), 9.25 (s, 1H). LC-MS: m/z 737 (M + H) Example 66 andN,N-diethyl-2- piperazin-1- ylethanamine 83

¹H NMR (400 MHz, CDCl₃): δ 1.24 (m, 6H), 1.99 (m, 2H), 2.03 (m, 2H),2.37 (s, 3H), 2.63 (m, 1H), 3.04 (m, 4H), 3.22 (m, 3H), 3.61 (m, 1H),3.85 (m, 2H), 4.22 (m, 6H), 4.42 (m, 1H), 7.22 (d, 1H), 8.18 (s, 1H),8.47 (s, 1H), 8.47 (s, 1H), 9.50 (s, 1H). LC-MS: m/z 649.82 (M + H)Example 66 and (3R)-3- methylpiperazine 84

¹H NMR (400 MHz, CDCl₃): δ 1.18 (t, 3H), 1.24 (t, 3H), 2.03 (m, 2H),2.27 (s, 3H), 2.64 (m, 6H), 3.22 (m, 2H), 3.41 (m, 2H), 3.61 (m, 1H),3.71 (m, 6H), 4.25 (m, 4H), 8.19 (s, 1H), 8.48 (s, 1H), 9.36 (s, 1H).LC-MS: m/z 681.50 (M + H) Example 66 and 2-piperazin-1- ylethanol 85

¹H NMR (400 MHz, CDCl₃): δ 1.22 (t, 3H), 1.31 (m, 3H), 1.35 (m, 2H),1.52 (m, 2H), 2.01 (m, 5H), 2.32 (s, 3H), 2.55 (m, 2H), 2.62 (m, 4H),3.21 (m, 2H), 3.45 (m, 1H), 3.81 (m, 8H), 4.22 (m, 2H), 4.45 (m, 1H),8.22 (s, 1H), 8.46 (s, 1H), 9.23 (s, 1H). LC-MS: m/z 721.5 (M + H)Example 66 and 1-(tetrahydrofuran- 2-ylmethyl)piper- azine

Example 862-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylicacid

To the solution of ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylate(Example 67, 120 mg, 0.188 mmol) in methanol (20 mL) was added 2N sodiumhydroxide (3 mL) in a dropwise fashion at 0° C. The reaction mixture wasstirred overnight and then concentrated under reduced pressure todryness. The resulting residue was diluted with water (20 mL) andextracted with ethyl acetate to remove any organic impurities. Theaqueous layer was passed through celite bed and acidified with 2Nhydrochloric acid. The precipitated product was collected by filtrationand dried to afford 35 mg (31.8%) of2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[5-(piperidin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylicacid as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.04 (t, 3H), 1.58 (m, 8H), 2.18 (s, 3H),3.44 (m, 2H), 3.46 (m, 1H), 3.75 (m, 8H), 4.27 (m, 1H), 7.14 (d, 1H),8.40 (s, 1H), 8.95 (s, 1H), 12.18 (s, 1H), 16.86 (s, 1H).

LC-MS: m/z 608.45 (M+H)

Examples 87-104

The following Examples were prepared according to the proceduredescribed for Example 86 from the starting material indicated in thetable.

Ex Compound Data SM 87

¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H), 1.78 (m, 2H), 2.18 (s, 3H),8.33 (m, 2H), 3.48 (m, 1H), 3.68 (m, 10H), 4.02 (m, 1H), 4.27 (m, 2H),7.13 (d, 1H), 8.41 (s, 1H), 8.98 (s, 1H), 12.15 (s, 1H), 16.67 (s, 1H).LC-MS: m/z 610.42 (M + H) Ex- ample 68 88

¹H NMR (400 MHz, DMSO- d₆): δ 1.03 (t, 3H), 1.78 (m, 2H), 2.18 (s, 3H),2.23 (s, 3H), 2.50 (m, 4H), 3.44 (m, 4H), 3.66 (m, 6H), 4.02 (m, 1H),4.26 (m, 1H), 7.13 (d, 1H), 8.43 (s, 1H), 9.00 (s, 1H), 12.16 (s, 1H).LC-MS: m/z 623.44 (M + H) Ex- ample 69 89

¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H), 1.78 (m, 2H), 2.18 (s, 3H),2.82 (m, 4H), 3.44 (m, 3H) 3.71 (m, 6H), 4.00 (m, 1H), 4.26 (m, 2H),7.12 (d, 1H), 8.39 (s, 1H), 8.99 (s, 1H), 12.15 (s, 1H). LC-MS: m/z609.39 (M + H) Ex- ample 70 90

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (t, 3H), 1.88 (m, 2H), 2.18 (s, 3H),3.45 (m, 6H), 3.48 (m, 5H), 3.64 (m, 1H), 3.96 (m, 1H), 4.24 (m, 2H),7.16 (d, 1H), 7.76 (s, 1H), 7.97 (s, 1H), 8.77 (s, 1H), 12.22 (s, 1H).LC-MS: m/z 598.43 (M + H) Ex- ample 71 91

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (t, 3H), 1.75 (m, 2H), 2.18 (s, 3H),2.41 (m, 4H), 3.44 (m, 13H), 3.91 (m, 1H), 4.23 (m, 2H), 7.2 (d, 1H),7.96 (s, 1H), 8.58 (s, 1H), 12.42 (s, 1H). LC-MS: m/z 653.60 (M + H) Ex-ample 72 92

¹H NMR (400 MHz, DMSO- d₆): δ 0.95 (t, 3H), 1.79 (m, 2H), 2.21 (s, 3H),3.41 (m, 6H), 3.45 (2s, 6H), 3.75 (m, 2H), 4.01 (m, 1H), 4.31 (m, 3H),7.15 (d, 1H), 8.02 (m, 2H), 8.95 (s, 1H), 12.19 (s, 1H). LC-MS: m/z642.45 (M + H) Ex- ample 73 93

¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (t, 3H), 1.76 (m, 2H), 2.18 (s, 3H),3.30 (m, 4H), 3.41 (m, 6H), 3.65 (m, 3H), 3.90 (m, 1H), 4.22 (m, 2H),6.27 (s, 1H), 7.22 (d, 1H), 7.90 (s, 1H), 8.60 (s, 1H), 12.42 (s, 1H).LC-MS: m/z 652.47 (M + H) Ex- ample 74 94

¹H NMR (400 MHz, DMSO- d₆): δ 1.05 (t, 3H), 1.76 (m, 2H), 1.85 (s, 3H),2.18 (s, 6H), 2.44 (m, 2H), 3.42 (m, 5H), 3.70 (m, 2H), 3.99 (m, 1H),4.23 (m, 2H), 7.18 (d, 1H), 7.50 (m, 1H), 7.96 (s, 1H), 8.72 (s, 1H),12.26 (s, 1H). LC-MS: m/z 611.66 (M + H) Ex- ample 75 95

¹H NMR (400 MHz, DMSO- d₆): δ 1.03 (t, 3H), 1.77 (m, 2H), 2.18 (s, 3H),2.41 (s, 3H), 2.56 (m, 8H), 3.41 (m, 8H), 3.71 (m, 2H), 4.27 (m, 2H),7.17 (d, 1H), 7.79 (2s, 2H), 8.934 (s, 1H), 12.2 (s, 1H). LC-MS: m/z666.6 (M + H) Ex- ample 76 96

¹H NMR (400 MHz, DMSO- d₆): δ 0.86 (m, 6H), 1.04 (t, 3H), 1.77 (m, 3H),2.05 (m, 2H), 2.16 (s, 3H), 2.42 (m, 4H), 3.30 (m, 2H), 3.63 (m, 6H),3.89 (m, 2H), 4.22 (m, 2H), 7.24 (d, 1H), 8.25 (s, 1H), 8.64 (s, 1H),12.38 (s, 1H). LC-MS: m/z 667.3 (M + H) Ex- ample 77 97

¹H NMR (400 MHz, DMSO- d₆): δ 0.82 (m, 2H), 1.10 (t, 3H), 1.77 (m, 6H),2.15 (2s, 6H), 2.51 (m, 9H), 2.79 (m, 2H), 3.21 (m, 2H), 3.61 (m, 7H),3.85 (m, 1H), 4.21 (m, 2H), 7.30 (d, 1H), 8.19 (s, 1H), 8.52 (s, 1H).LC-MS: m/z 720.55 (M + H) Ex- ample 78 98

¹H NMR (400 MHz, DMSO- d₆): δ 0.81 (m, 2H), 1.02 (t, 3H), 1.63 (m, 9H),2.11 (m, 2H), 2.15 (s, 3H), 2.40 (m, 4H), 3.31 (m, 6H), 3.66 (m, 6H),3.87 (m, 1H), 4.22 (s, 1H), 7.26 (d, 1H), 8.21 (s, 1H), 8.57 (s, 1H),12.45 (s, 1H). LC-MS: m/z 705.68 (M + H) Ex- ample 79 99

¹H NMR (400 MHz, DMSO- d₆): δ 0.84 (m, 6H), 1.01 (t, 3H), 1.24 (m, 4H),1.44 (m, 1H), 1.76 (m, 2H), 2.16 (s, 3H), 2.55 (m, 4H), 3.44 (m, 4H),3.71 (m, 6H), 4.26 (2m, 2H), 7.13 (d, 1H), 8.4 (s, 1H), 8.98 (s, 1H),12.14 (s, 1H). LC-MS: m/z 681.44 (M + H) Ex- ample 80 100

¹H NMR (400 MHz, DMSO- d₆): δ 1.03 (m, 6H), 2.16 (s, 3H), 2.36 (m, 2H),2.47 (m, 4H), 3.25 (m, 4H), 3.41 (m, 2H), 3.68 (m, 6H), 3.85 (m, 1H),4.21 (m, 1H), 7.30 (d, 1H), 8.20 (s, 1H), 8.53 (s, 1H). LC-MS: m/z 637.3(M + H) Ex- ample 81 101

¹H NMR (400 MHz, DMSO- d₆): δ 0.93 (m, 6H), 1.02 (t, 3H), 2.16 (s, 3H),2.50 (m, 4H), 3.43 (m, 6H), 3.70 (m, 2H), 3.96 (m, 2H), 4.23 (s, 1H),4.25 (m, 2H), 7.15 (d, 1H), 8.36 (s, 1H), 8.88 (s, 1H), 12.23 (s, 1H).LC-MS: m/z 708.7 (M + H) Ex- ample 82 102

¹H NMR (400 MHz, DMSO- d₆): δ 1.04 (m, 6H), 1.90 (m, 2H), 2.18 (s, 3H),2.55 (m, 1H), 2.68 (m, 2H), 3.35 (m, 4H), 3.42 (m, 1H), 3.79 (m, 2H),4.02 (m, 1H), 4.29 (m, 4H) LC-MS: m/z 623.44 (M + H) Ex- ample 83 103

¹H NMR (400 MHz, DMSO- d₆): δ 1.06 (t, 3H), 1.76 (m, 2H), 2.18 (s, 3H),2.52 (m, 4H), 3.42 (m, 5H), 3.91 (m, 1H), 4.23 (m, 2H), 7.22 (d, 1H),8.29 (s, 1H), 8.71 (s, 1H), 12.12 (s, 1H). LC-MS: m/z 653.47 (M + H) Ex-ample 84 104

¹H NMR (400 MHz, DMSO- d₆): δ 1.02 (t, 3H), 1.44 (m, 1H), 1.74 (m, 4H),1.93 (m, 2H), 2.16 (s, 3H), 2.39 (m, 2H), 2.41 (m, 4H), 2.61 (m, 2H),3.32 (m, 4H), 3.47 (m, 2H), 3.73 (m, 4H), 3.93 (m, 1H), 4.24 (m, 1H),7.19 (d, 1H), 8.32 (s, 1H), 8.81 (s, 1H), 12.28 (s, 1H). LC-MS: m/z693.3 (M + H) Ex- ample 85

Examples 105-123

The following Examples were prepared according to the proceduredescribed for Example 60 from the starting material listed in the table.

Ex Compound Data SM 105

¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (m, 4H), 1.14 (t, 3H), 1.55-1.76 (m,8H), 2.19 (s, 3H), 3.28-3.33 (m, 4H), 3.55 (m, 1H), 3.64 (m, 2H), 4.10(m, 2H), 4.27 (m, 2H), 7.16 (d, 1H), 8.30 (s, 2H), 12.12 (s, 1H). MASS(APCI −ve Scan) m/z 620 (M − H) Example 60 and piperidine 106

¹H NMR (400 MHz, DMSO-d₆): δ 1.14 (t, 3H), 1.77 (m, 2H), 2.18 (s, 3H),3.36 (m, 5H), 3.60 (m, 6H), 3.72 (m, 4H), 4.10 (m, 2H), 4.27 (m, 2H),7.15 (d, 1H), 8.34 (d, 2H), 12.13 (s, 1H). MASS (APCI +ve Scan) m/z 624(M + H) Example 60 and morpholine 107

¹H NMR (400 MHz, CDCl₃): δ 1.27 (m, 6H), 1.41 (m, 9H), 1.90 (m, 1H),2.06 (m, 1H), 2.27 (s, 3H), 3.22 (m, 3H), 3.56 (m, 9H), 4.03-4.32 (m,4H), 4.50 (m, 1H), 7.23 (m, 1H), 8.18 (s, 1H), 8.49 (s, 1H). LC-MS: m/z723.51 (M + H) Example 60 and 4-boc- piperidine [PI- PERA- ZINE??] 108

¹H NMR (400 MHz, DMSO-d₆): δ 1.13 (t, 3H), 1.76 (m, 2H), 1.91 (t, 3H),2.17 (m, 6H), 2.69 (m, 1H), 3.40-3.52 (m, 10H), 4.10 (m, 2H), 4.26 (m,2H), 7.16 (d, 1H), 7.39 (s, 1H), 7.91 (s, 1H), 8.21 (s, 1H), 12.21 (brs, 1H). MASS (APCI −ve Scan) m/z 663 (M − H) Example 60 and 1-(2-aminoethyl) pyrrolidin- 2-one 109

¹H NMR (400 MHz, DMSO-d₆): δ 1.12 (t, 3H), 1.76 (m, 2H), 2.18 (s, 3H),3.22 (m, 4H), 3.48 (s, 4H), 3.55 (s, 1H), 3.96 (br s, 1H), 4.09 (m, 2H),4.26 (br s, 2H), 7.16 (d, 1H), 7.44 (s, 1H), 7.96 (s, 1H), 8.19 (s, 1H),12.14 (br s, 2H). MASS (APCI −ve Scan) m/z 610 (M − H) Example 60 and2-methoxy- ethylamine 110

¹H NMR (400 MHz, CDCl₃): δ 1.25 (m, 5H), 1.42 (m, 1H), 1.89 (m, 2H),2.27 (s, 3H), 3.20 (m, 2H), 3.42 (m, 10H), 4.09 (m, 6H), 4.33 (m, 1H),5.12 (m, 1H), 7.22 (m, 1H), 7.96 (s, 1H), 8.41 (s, 1H), 9.36 (brs, 1H)LC-MS: m/z 656 (M + H) Example 60 and 1,3- dimethoxy- propylamine 111

¹H NMR (400 MHz, CDCl₃): δ 0.87 (m, 3H), 1.23 (m, 4H), 1.86 (m, 2H),2.27 (s, 3H), 2.43 (m, 3H), 2.64 (m, 2H), 3.22 (m, 2H), 3.48 (m, 3H),3.74 (m, 3H), 4.23 (m, 3H), 4.49 (d, 1H), 5.39 (brs, 1H), 7.23 (m, 1H),7.98 (s, 1H), 8.41 (s, 1H), 8.41 (s, 1H), 9.5 (brs, 1H). LC-MS: m/z667.4 (M + H) Example 60 and morpholi-4- ethylamine 112

¹H NMR (400 MHz, CDCl₃): δ 1.25 (m, 6H), 1.92-2.04 (m, 3H), 2.27 (s,3H), 3.18 (m, 2H), 3.43 (m, 8H), 4.09-4.49 (m, 6H), 5.49 (m, 1H), 7.22(m, 1H), 7.96 (s, 1H), 8.40 (s, 1H), 9.45 (brs, 1H). LC-MS: m/z 666 (M +H) Example 60 and 1-(2-amino- ethyl)imido- 2-one 113

¹H NMR (400 MHz, CDCl₃): 1.26 (m, 3H), 1.86 (m, 3H), 2.27 (m, 9H), 2.59(m, 2H), 3.21 (m, 2H), 3.49 (m, 6H), 4.09 (m, 1H), 4.21 (m, 2H), 4.31(m, 1H), 4.49 (m, 1H), 7.26 (m, 1H), 7.97 (s, 1H), 8.41 (s, 1H), 9.53(brs, 1H). LC-MS: m/z 625.45 (M + H) Example 60 and N,N- dimethyl-aminoethyl- amine 114

¹H NMR (400 MHz, DMSO-d₆): δ 1.21 (t, 3H), 1.28 (m, 3H), 1.81 (m, 2H),2.22 (s, 3H),, 3.04 (m, 4H), 3.21- 3.56 (m, 14H), 3.98 (m, 1H), 4.12 (q,2H), 4.34 (m, 2H), 7.18 (d, 1H), 7.25 (d, 1H), 7.96 (s, 1H), 8.22 (s,1H), 12.18 (s, 1H) LC-MS: m/z 680 (M + H) Example 60 and N-methyl-piperdin-4- amine 115

LC-MS: m/z 679 (M + H) Example 60 and 2- methyl- propyl4- piperidine 116

¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (t, 3H), 1.3-1.82 (7H), 2.21 (s, 3H),2.24 (m, 4H), 2.56 (s, 3H), 2.58 (m, 6H), 2.61-2.98 (m, 4H), 3.2-3.72(m, 6H), 3.98 (d, 1H), 4.14 (q, 2H), 4.36 (s, 2H), 7.18 (d, 1H), 8.36(s, 2H), 12.18 (s, 1H). LC-MS: m/z 734.34 (M + H) Example 60 and 1-methyl- piperidin-3- methyl- piperazine 117

¹H NMR (400 MHz, DMSO-d₆): δ 0.90 (m, 3H), 1.23 (m, 4H), 1.73 (m, 8H),2.00 (m, 4H), 2.18 (s, 3H), 2.48 (m, 4H), 3.18 (m, 2H), 3.43 (m, 3H),3.65 (m, 4H), 4.06 (m, 1H), 4.20 (m, 3H), 4.54 (m, 1H), 7.26 (m, 1H),8.17 (s, 1H), 8.47 (s, 1H), 9.43 (brs, 1H). LC-MS: m/z (M + H) Example60 and cyclohexyl- methyl- piperidine 118

¹H NMR (400 MHz, DMSO-d₆): δ 0.92 (t, 6H), 1.21 (t, 3H), 1.45 (m, 2H),1.61- 1.81 (m, 5H), 2.16- 2.25 (m, 4H), 2.62 (m, 4H), 3.21-3.56 (m,10H), 3.81 (m, 2H), 4.18 (m, 3H), 7.40 (brs, 1H), 8.20 (s, 1H), 8.45 (s,1H). LC-MS: m/z 693 (M + H) Example 60 and 1-(1-ethyl- propyl)piperazine 119

¹H NMR (400 MHz, CDCl₃): δ 1.00 (m, 3H), 1.13 (m, 3H), 1.86 (m, 2H),2.27 (s, 3H), 2.46 (m, 4H), 3.22 (m, 2H), 3.46 (m, 6H), 3.69 (m, 4H),4.23 (m, 4H), 4.50 (m, 1H), 7.26 (m, 1H), 8.18 (s, 1H), 8.48 (s, 1H),9.33 (brs, 1H). LC-MS: m/z 651.40 (M + H) Example 60 and ethyl-piperazine 120

¹H NMR (400 MHz, DMSO-d₆): δ 0.99 (t, 6H), 1.22 (t, 3H), 1.81 (d, 2H),2.18 (s, 3H), 2.51-3.82 (m, 8H), 3.21-3.42 (m, 9H), 3.42-3.78 (m, 5H),3.98 (m, 1H), 4.18 (q, 2H), 4.34 (d, 2H), 7.19 (d, 1H), 8.37 (s, 2H),12.19 (s, 1H). LC-MS: m/z 722. (M + H) Example 60 and 2- diethyl-aminoethyl- piperazine 121

¹H NMR (400 MHz, CDCl₃): δ 1.21 (m, 6H), 1.89-2.05 (m, 3H), 2.27 (s,3H), 2.70 (m, 1H), 2.95-3.33 (m, 6H), 3.51 (m, 4H), 4.02- 4.32 (m, 6H),4.50 (m, 1H), 7.26 (m, 1H), 8.18 (s, 1H), 8.48 (s, 1H), 9.44 (brs, 1H).LC-MS: m/z 637 (M + H) Example 60 and (3R)-3- methyl- piperazine 122

¹H NMR (400 MHz, CDCl₃): δ 1.25 (m, 2H), 1.86 (m, 2H), 1.90 (m, 2H),2.09 (s, 3H), 2.65 (m, 6H), 3.18 (m, 2H), 3.46 (m, 4H), 3.74 (m, 6H),4.06 (m, 1H), 4.23 (m, 2H), 4.32 (m, 1H), 4.50 (m, 1H), 7.26 (m, 1H),8.19 (s, 1H), 8.49 (s, 1H), 9.44 (brs, 1H). LC-MS: m/z 667.62. (M + H)Example 60 and 2-hydroxy- ethyl- piperazine 123

LC-MS: m/z 707 (M + H) Example 60 and 1- (tetrahydro- furan-2-yl-methyl) piperazine

Examples 124-142

The following Examples were prepared according to the procedure forExample 61 from the starting material indicated in the table.

Ex Compound Data SM 124

¹H-NMR (400 MHz, DMSO- d₆): δ 1.58 (m, 6H), 1.76 (s, 2H), 1.87 (s, 2H),2.18 (s, 3H), 3.37 (m, 4H), 3.54 (s, 1H), 3.66 (s, 3H), 4.25 (d, 2H),7.25 (d, 1H), 8.33 (d, 1H), 8.80 (br s, 1H), 12.32 (br s, 1H). LC-MS:m/z 594.3 (M + H) Ex- ample 105 125

¹H-NMR (400 MHz, DMSO- d₆): δ 1.77 (m, 2H), 2.18 (s, 3H), 3.38 (m, 4H),3.55 (m, 1H), 3.71 (m, 8H), 3.94 (br s, 2H), 4.77 (d, 1H), 7.20 (d, 1H),8.40 (s, 1H), 8.95 (s, 1H), 12.21 (br s, 2H). LC-MS: m/z 596.3 (M + H)Ex- ample 106 126

¹H-NMR (400 MHz, DMSO- d₆): δ 1.78 (m, 2H), 2.18 (s, 3H), 3.17 (m, 3H),3.35 (m, 9H), 3.57 (m, 1H), 3.91 (m, 4H), 4.27 (m, 2H), 7.15 (d, 1H),8.50 (s, 1H), 9.03 (s, 1H), 12.16 (brs, 1H). LC-MS: m/z 595.47 (M + H)Ex- ample 107 127

¹H-NMR (400 MHz, DMSO- d₆): δ 1.78 (m, 2H), 1.88 (m, 2H), 2.61 (m, 5H),3.30 (m, 9H), 3.52 (m, 3H), 4.02 (br s, 2H), 4.27 (m, 2H), 7.16 (d, 1H),7.99 (d, 2H), 8.95 (s, 1H), 12.14 (s, 1H). LC-MS: m/z 637.2 (M + H) Ex-ample 108 128

¹H-NMR (400 MHz, DMSO- d₆): δ 1.77 (s, 3H), 2.18 (s, 3H), 3.33 (m, 3H),3.39 (m, 5H), 3.52 (m, 5H), 3.96 (br s, 2H), 4.27 (d, 1H), 4.49 (br s,1H), 7.16 (d, 1H), 8.01 (d, 1H), 8.95 (s, 1H), 12.15 (s, 1H). LC-MS: m/z584.2 (M + H) Ex- ample 109 129

¹H-NMR (400 MHz, DMSO- d₆): δ 1.77 (m, 2H), 2.18 (s, 3H), 3.37 (m, 14H),3.89 (m, 2H), 4.29 (m, 4H), 7.24 (d, 1H), 7.99 (s, 1H), 7.59 (brs, 1H),8.75 (brs, 1H), 12.28 (brs, 1H). LC-MS: m/z 628.43 (M + H) Ex- ample 110130

¹H-NMR (400 MHz, DMSO- d₆): δ 1.74 (m, 2H), 2.18 (s, 3H), 2.50 (m, 5H),3.26 (m, 5H), 3.43 (m, 4H), 3.56 (m, 5H), 3.88 (brs, 1H), 4.25 (m, 2H),7.28 (m, 1H), 8.64 (brs, 1H), 12.41 (brs, 1H) LC-MS: m/z 639.37 (M + H)Ex- ample 111 131

¹H-NMR (400 MHz, DMSO- d₆): δ 1.76 (m, 3H), 2.18 (s, 3H), 3.18 (m, 15H),3.91 (brs, 1H), 4.26 (m, 2H), 6.27 (m, 1H), 7.22 (d, 1H), 7.94 (s, 1H),8.79 (brs, 1H), 12.28 (brs, 1H). LC-MS: m/z 638.42 (M + H) Ex- ample 112132

¹H-NMR (400 MHz, DMSO- d₆): δ 1.78 (m, 2H), 2.18 (s, 3H), 2.81 (s, 6H),3.21-3.41 (m, 8H), 3.57 (brs, 1H), 3.73 (m, 2H), 4.27 (m, 1H), 7.20 (m,1H), 8.06 (s, 1H), 8.27 (brs, 1H), 8.97 (s, 1H), 10.12 (brs, 1H), 12.20(s, 1H). LC-MS: m/z 597.53 (M + H) Ex- ample 113 133

¹H-NMR (400 MHz, DMSO- d₆): δ 1.76 (d, 2H), 2.16 (s, 3H) 2.65 (s, 9H),3.21-3.62 (m, 12H), 3.97 (d, 1H), 4.24 (d, 1H), 4.45 (d, 1H), 4.45 (d,1H), 7.13 (d, 1H), 7.85 (d, 1H), 7.99 (s, 1H), 7.93 (s, 1H), 12.13 (s,1H). LC-MS: m/z 652.6 (M + H) Ex- ample 114 134

¹H-NMR (400 MHz, DMSO- d₆): δ 0.85 (d, 6H), 1.78 (m, 2H), 2.14 (m, 4H),2.9 (m, 2H), 3.05-3.67 (m, 14H), 4.31 (m, 1H), 4.54 (m, 2H), 7.18 (d,1H), 8.55 (s, 1H), 9.05 (s, 1H), 12.18 (s, 1H). LC-MS: m/z 651 (M + H)Ex- ample 115 135

¹H-NMR (400 MHz, DMSO- d₆): δ 1.3-1.82 (7H), 2.21 (s, 3H), 2.24 (m, 4H),2.56 (s, 3H), 2.58 (m, 6H), 2.61-2.98 (m, 4H), 3.2-3.72 (m, 7H), 3.98(d, 1H), 4.36 (d, 2H), 7.18 (d, 1H), 8.36 (s, 2H), 12.18 (s, 1H). LC-MS:m/z 708 (M + H) Ex- ample 116 136

¹H-NMR (400 MHz, DMSO- d₆): δ 0.95 (m, 2H), 1.19 (m, 4H), 1.61 (m, 8H),2.18 (s, 3H), 3.11 (m, 3H), 3.39 (m, 8H), 3.61 (m, 4H), 4.27 (m, 1H),4.51 (m, 2H), 7.20 (m, 1H), 8.54 (s, 1H), 9.05 (s, 1H), 10.41 (brs, 1H),12.20 (s, 1H). LC-MS: m/z 691.58 (M + H) Ex- ample 117 137

¹H-NMR (400 MHz, DMSO- d₆): δ 0.86 (t, 6H), 1.26 (t, 3H), 1.42 (m, 4H),2.18 (s, 3H), 2.21 (s, 1H), 2.54 (s, 3H), 3.12- 3.50 (m, 10H), 3.81 (d,2H), 4.14 (d, 2H), 7.3 (d, 1H), 8.19 (s, 1H), 8.48 (s, 1H), 12.18 (s,1H). LC-MS: m/z 665 (M + H) Ex- ample 118 138

¹H-NMR (400 MHz, DMSO- d₆): δ 1.25 (m, 3H), 1.78 (m, 2H), 2.18 (s, 3H),3.12 (m, 4H), 3.32 (m, 9H), 4.29 (m, 4H), 4.58 (m, 2H), 7.19 (m, 1H),8.55 (s, 1H), 9.05 (s, 1H), 10.61 (brs, 1H), 12.18 (s, 1H). LC-MS: m/z623.37 (M + H) Ex- ample 119 139

¹H-NMR (400 MHz, DMSO- d₆): δ 0.99 (t, 6H), 1.81 (m, 2H), 2.18 (s, 3H),2.41-2.60.81 (m, 12H), 3.21-3.78 (m, 13H), 4.22 (m, 1H), 7.18 (d, 1H),8.42 (s, 1H), 9.02 (s, 1H), 12.19 (s, 1H). LC-MS: m/z 623 (M + H) Ex-ample 120 140

¹H-NMR (400 MHz, DMSO- d₆): δ 1.02 (d, 3H), 1.76 (m, 7H), 2.18 (s, 3H),2.40 (m, 1H), 2.71 (m, 3H), 2.93 (d, 1H), 3.22 (m, 2H), 3.50 (m, 2H),3.80 (m, 1H), 4.15 (m, 4H), 7.46 (brs, 1H), 8.19 (s, 1H), 8.50 (s, 1H)LC-MS: m/z 609 43 (M + H) Ex- ample 121 141

¹H-NMR (400 MHz, DMSO- d₆): δ 1.80 (m, 3H), 2.19 (m, 3H), 2.45 (m, 3H),3.25 (m, 8H), 3.55 (m, 7H), 3.91 (brs, 1H), 4.21 (m, 2H), 4.24 (brs,1H), 7.31 (brs, 1H), 8.27 (s, 1H), 8.72 (s, 1H), 12.59 (brs, 1H). LC-MS:m/z 639.49 (M + H) Ex- ample 122 142

¹H-NMR (400 MHz, DMSO- d₆): δ 1.21 (d, 2H), 1.72 (s, 4H), 1.92 (s, 4H),2.18 (s, 2H), 2.54 (d, 4H), 3.32 (m, 3H), 3.51-4.22 (m, 9H), 4.51 (m,4H), 7.24 (d, 1H), 8.49 (s, 1H), 9.03 (s, 1H), 12.21 (s, 1H) LC-MS: m/z679.63 (M + H) Ex- ample 123

Example 143

Ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-1,3-thiazole-5-carboxylate

To a stirred solution of ethyl2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate(Intermediate 47, 1.8 g, 5.142 mmol), and3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide(Intermediate 39, 1.47 g, 5.142 mmol) in N-methyl 2-pyrrolidinone (1 mL)was added N,N-Diisopropylethylamine (1.7 mL, 10.284 mmol) at roomtemperature. The reaction mixture was heated to 50° C. for 5 h. Thereaction mixture was cooled to room temperature, water (60 mL) wasadded, the precipitated product was collected by filtration, washed withwater and dried to afford 2.2 g (78%) of ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-1,3-thiazole-5-carboxylate.

¹H NMR (400 MHz, CDCl₃): δ 0.93 (m, 3H), 1.11 (t, 3H), 1.82 (m, 2H),2.07 (s, 4H), 3.60 (m, 4H), 4.09 (q, 2H), 4.25 (m, 1H), 7.21 (d, 1H),8.76 (d, 1H), 8.86 (d, 1H), 12.03 (s, 1H);

LC-MS: m/z 557 (M+H).

Examples 144-163

The following Examples were prepared according to the proceduredescribed for Example 60 from the starting materials indicated.

Ex Compound Data SM 144 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Example dichloro-5-methyl-1H- d₆): δ 1.58 (m, 6H), 1.76 (s, 143and pyrrol-2- 2H), 1.87 (s, 2H), 2.18 (s, 3H), ethyl-yl)carbonyl]amino}-3- 3.37 (m, 4H), 3.54 (s, 1H), piper-methylpiperidin-1-yl]-4-[5- 3.66 (s, 3H), 4.25 (d, 2H), 7.25 idine(4-ethylpiperazin-1- (d, 1H), 8.33 (d, 1H), 8.80 (bryl)pyrazin-2-yl]-1,3- s, 1H), 12.32 (br s, 1H). thiazole-5-carboxylateLC-MS: m/z 594.3 (M + H)

145 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.14 (t, 143 and pyrrol-2-3H), 1.56 (m, 6H), 1.81 (m, piper- yl)carbonyl]amino}-3- 2H), 2.19 (s,4H), 3.61 (m, idine methylpiperidin-1-yl]-4-[5- 8H), 4.08 (m, 2H), 4.25(s, (piperidin-1-yl)pyrazin-2- 1H), 7.20, (d, 1H), 8.30 (s,yl]-1,3-thiazole-5- 2H), 12.04 (s, H). carboxylate LC-MS: m/z 606 (M +H)

146 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.14 (t, 143 and pyrrol-2-3H), 1.82 (m, 2H), 2.18 (s, morpho- yl)carbonyl]amino}-3- 4H), 3.56 (m,7H), 3.72 (m, line methylpiperidin-1-yl]-4-[5- 5H), 4.09 (m, 2H), 4.25(m, (morpholin-4-yl)pyrazin-2- 1H), 7.20 (d, 1H), 8.32 (d, 1H),yl]-1,3-thiazole-5- 8.34 (d, 1H), 12.03 (s, 1H). carboxylate LC-MS: m/z608 (M + H)

147 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.91 (d, 3H), 1.14 (t, 143 and pyrrol-2-3H), 1.79 (m, 2H), 2.19 (m, methyl- yl)carbonyl]amino}-3- 7H), 2.39 (s,4H), 3.53 (m, piper- methylpiperidin-1-yl]-4-[5- 8H), 4.08 (m, 2H), 4.23(m, azine (4-methylpiperazin-1- 1H), 7.22 (d, 1H), 8.30 (s, 2H),yl)pyrazin-2-yl]-1,3- 12.08 (s, 1H). thiazole-5-carboxylate LC-MS: m/z621.3 (M + H)

148 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.13 (t, 143 and pyrrol-2-3H), 1.81 (m, 2H), 2.19 (s, piper- yl)carbonyl]amino}-3- 4H), 3.85 (t,3H), 3.40 (m, azine methylpiperidin-1-yl]-4-[5- 4H), 3.63 (m, 6H), 4.10(m, (piperazin-1-yl)pyrazin-2- 2H) 4.25 (m, 1H), 7.23 (d,yl]-1,3-thiazole-5- 1H), 8.30 (s, 1H), 8.32 (s, 1H), carboxylate 12.12(s, 1H).

LC-MS: m/z 607 (M + H) 149 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Example dichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.15 (t, 143and pyrrol-2- 3H), 1.86 (m, 4H), 2.15 (m, 1-(2- yl)carbonyl]amino}-3-5H), 3.40 (m, 7H), 3.62 (m, amino- methylpiperidin-1-yl]-4-(5- 4H), 4.09(m, 2H), 4.24 (s, ethyl) {[2-(2-oxopyrrolidin-1- 1H), 7.20 (d, 1H), 7.40(t, 1H), imido-2- yl)ethyl]amino}pyrazin-2- 7.90 (d, 1H), 8.21 (d, 1H),one yl)-1,3-thiazole-5- 12.04 (s, 1H). carboxylate LC-MS: m/z 649.3 (M +H)

150 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (t, 3H), 1.15 (m, 143 and pyrrol-2-3H), 1.81 (m, 2H), 2.19 (s, 2-meth- yl)carbonyl]amino}-3- 4H), 3.28 (s,3H), 3.52 (m, oxy- methylpiperidin-1-yl]-4-{5- 5H), 3.69 (m, 3H), 4.08(m, ethyl- [(2- 2H), 4.25 (s, 1H), 7.20 (d, 1H), aminemethoxyethyl)amino]pyrazin- 7.43 (s, 1H), 7.96 (s, 1H), 8.192-yl}-1,3-thiazole-5- (s, 1H), 12.03 (s, 1H). carboxylate LC-MS: m/z596.2 (M + H)

151 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.16 (t, 143 and pyrrol-2-3H), 1.81 (m, 2H), 2.19 (s, morph- yl)carbonyl]amino}-3- 4H), 2.42 (s,4H), 3.44 (m, olin- methylpiperidin-1-yl]-4-(5- 4H), 3.60 (m, 8H), 4.10(m, 4- {[2-(morpholin-4- 2H), 4.26 (s, 1H), 7.19 (d, 1H), ethyl-yl)ethyl]amino}pyrazin-2- 7.25 (m, 1H), 7.96 (d, 1H), amineyl)-1,3-thiazole-5- 8.20 (s, 1H), 12.02 (s, 1H) carboxylate LC-MS: m/z651.13 (M + H)

152 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, CDCl₃): δ Exampledichloro-5-methyl-1H- 1.02 (m, 3H), 1.93 (m, 2H), 143 and pyrrol-2- 2.24(s, 3H), 2.25 (m, 2H), 1,3- yl)carbonyl]amino}-3- 3.33 (s, 6H), 3.49 (m,6H), dimeth- methylpiperidin-1-yl]-4-{5- 3.75 (m, 2H), 3.77 (m, 1H),oxy- [(1,3-dimethoxypropan-2- 4.24 (m, 2H), 4.31 (m, 1H), proan-yl)amino]pyrazin-2-yl}-1,3- 4.40 (m, 1H), 5.12 (d, 1H), 2-aminethiazole-5-carboxylate 6.77 (d, 1H), 7.97 (s, 1H), 8.43

(s, 1H), 9.27 (s, 1H). LC-MS: m/z 640.44 (M + H) 153 Ethyl2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (m, 3H), 1.23 (t, 143 and pyrrol-2-3H), 1.81 (m, 2H), 2.19 (s, 2-oxo- yl)carbonyl]amino}-3- 4H), 3.19 (m,4H), 3.42 (m, imida- methylpiperidin-1-yl]-4-(5- 5H), 3.62 (m, 3H), 4.09(q, zol- {[2-(2-oxoimidazolidin-1- 2H), 4.25 (s, 1H), 6.31 (s, 1H),indin-1- yl)ethyl]amino}pyrazin-2- 7.20 (d, 1H), 7.41 (t, 1H), 7.93ethyl- yl)-1,3-thiazole-5- (s, 1H), 8.21 (s, 1H), 12.04 (s, amiecarboxylate 1H).

LC-MS: m/z 650 (M + H) 154 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Example dichloro-5-methyl-1H- d₆): δ 0.91 (t, 3H), 1.15 (m, 143and pyrrol-2- 3H), 1.80 (m, 2H), 2.19 (d, N,N- yl)carbonyl]amino}-3-9H), 2.49 (m, 2H), 3.42 (m, dimeth- methylpiperidin-1-yl]-4-(5- 3H),3.55 (m, 4H), 4.08 (m, yl- {[2- 2H), 4.25 (s, 1H), 7.21 (d, 1H), amino-(dimethylamino)ethyl]amino} 7.27 (t, 1H), 7.96 (d, 1H), 8.20 ethyl-pyrazin-2-yl)-1,3-thiazole- (d, 1H), 12.05 (s, 1H). amine 5-carboxylateLC-MS: m/z 609.3 (M + H)

155 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, CDCl₃): δ Exampledichloro-5-methyl-1H- 1.04 (m, 3H), 1.29 (m, 6H), 143 and pyrrol-2- 2.02(m, 2H), 2.33 (m, 6H), 4- yl)carbonyl]amino}-3- 2.64 (m, 8H), 3.35 (m,1H), methyl- methylpiperidin-1-yl]-4-(5- 3.48 (m, 2H), 3.62 (m, 1H),piper- {[2-(4-methylpiperazin-1- 3.76 (m, 2H), 4.22 (m, 2H), azine-1-yl)ethyl]amino}pyrazin-2- 4.41 (brs, 1H), 5.44 (m, 1H), ethyl-yl)-1,3-thiazole-5- 6.81 (d, 1H), 7.97 (s, 1H), 8.43 amine carboxylate(s, 1H), 9.78 (brs, 1H).

LC-MS: m/z 664.50 (M + H) 156 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400MHz, DMSO- Example dichloro-5-methyl-1H- d₆): δ 0.89 (m, 9H), 1.12 (m,143 and pyrrol-2- 3H), 1.80 (m, 3H), 2.08 (d, 2- yl)carbonyl]amino}-3-2H), 2.18 (s, 4H), 2.44 (m, meth- methylpiperidin-1-yl]-4-{5- 4H), 3.56(m, 8H), 4.09 (m, yl- [4-(2- 2H), 4.25 (s, 1H), 7.20 (d, 1H), propyl-methylpropyl)piperazin-1- 8.31 (d, 2H), 12.03 (s, 1H), piper-yl]pyrazin-2-yl}-1,3- LC-MS: m/z 663.3 (M + H) azinethiazole-5-carboxylate

157 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, CDCl₃): δ Exampledichloro-5-methyl-1H- 1.04 (m, 3H), 1.27 (m, 10H), 143 and pyrrol-2-1.41 (m, 4H), 1.88 (m, 4H), 1-meth- yl)carbonyl]amino}-3- 2.02 (m, 7H),2.44 (m, 4H), ylpiper- methylpiperidin-1-yl]-4-(5- 3.31 (m, 1H), 3.61(m, 6H), idin- {4-[(1-methylpiperidin-3- 4.18 (m, 2H), 4.40 (brs, 1H),3- yl)methyl]piperazin-1- 6.76 (d, 1H), 8.17 (s, 1H), 8.49 methyl-yl}pyrazin-2-yl)-1,3- (s, 1H), 9.34 (s, 1H). piper-thiazole-5-carboxylate LC-MS: m/z 718.53 (M + H) azine

158 Ethyl 4-{5-[4- ¹H NMR (400 MHz, DMSO- Example(cyclohexylmethyl)piperazin- d₆): δ 0.83 (m, 3H), 0.91 (t, 143 and1-yl]pyrazin-2-yl}-2- 3H), 1.14 (m, 4H), 1.51 (m, cyclo-[(3S,4R)-4-{[(3,4-dichloro- 9H), 2.10 (d, 2H), 2.17 (s, 4H), hexyl-5-methyl-1H-pyrrol-2- 2.41 (t, 4H), 3.55 (m, 8H), 4.07 meth-yl)carbonyl]amino}-3- (m, 2H), 4.23 (s, 1H), 7.18 (d, yl-methylpiperidin-1-yl]-1,3- 1H), 8.29 (s, 1H), 8.30 (s, 1H), piper-thiazole-5-carboxylate 12.01 (s, 1H). azine

LC-MS: m/z 703.4 (M + H) 159 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Example dichloro-5-methyl-1H- d₆): δ 0.90 (m, 9H), 1.14 (t, 143and pyrrol-2- 3H), 1.28 (m, 2H), 1.47 (m, 4- yl)carbonyl]amino}-3- 2H),1.81 (m, 2H), 2.21 (m, pentan- methylpiperidin-1-yl]-4-{5- 5H), 2.56 (m,4H), 3.55 (m, 3- [4-(pentan-3-yl)piperazin-1- 8H), 4.09 (m, 2H), 4.25(s, piper- yl]pyrazin-2-yl}-1,3- 1H), 7.20 (d, 1H), 8.30 (s, 1H), azinethiazole-5-carboxylate 8.31 (s, 1H), 12.04 (s, 1H).

LC-MS: m/z 677.4 (M + H) 160 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,CDCl₃): δ Example dichloro-5-methyl-1H- 1.02 (m, 7H), 1.28 (m, 10H), 143and pyrrol-2- 1.94 (m, 2H), 2.25 (m, 4H), 2- yl)carbonyl]amino}-3- 2.60(m, 4H), 3.30 (m, diethyl- methylpiperidin-1-yl]-4-(5- 1H),3.60 (m, 6H),4.18 (m, amino- {4-[2- 2H), 4.40 (brs, 1H), 6.79 (d, ethyl-(diethylamino)ethyl]piperazin- 1H), 8.18 (s, 1H), 8.50 (s, piper-1-yl}pyrazin-2-yl)-1,3- 1H). 9.71 (brs, 1H). azinethiazole-5-carboxylate LC-MS: m/z 706.76 (M + H)

161 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Exampledichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.03 (d, 143 and pyrrol-2-3H), 1.14 (t, 3H), 1.81 (m, (3R)-3- yl)carbonyl]amino}-3- 2H), 2.18 (s,4H), 2.72 (m, methyl- methylpiperidin-1-yl]-4-{5- 2H), 2.82 (m, 1H),2.96 (d, piper- [(3R)-3-methylpiperazin-1- 1H), 3.55 (m, 6H), 4.08 (q,azine yl]pyrazin-2-yl}-1,3- 2H), 4.23 (m, 3H), 7.21 (d,thiazole-5-carboxylate 1H), 8.30 (s, 2H), 12.04 (s,

1H). LC-MS: m/z 621.4 (M + H) 162 Ethyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400MHz, DMSO- Example dichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.14 (t,143 and pyrrol-2- 3H), 1.81 (m, 2H), 2.18 (s, 2- yl)carbonyl]amino}-3-4H), 2.43 (t, 2H), 2.51 (m, hydroxy- methylpiperidin-1-yl]-4-{5- 4H),3.55 (m, 9H), 3.71 (m, ethyl- [4-(2- 1H), 4.11 (q, 2H), 4.25 (m, aminehydroxyethyl)piperazin-1- 1H), 4.47 (t, 1H), 7.21 (d, 1H),yl]pyrazin-2-yl}-1,3- 8.32 (s, 2H), 12.05 (s, 1H).thiazole-5-carboxylate LC-MS: m/z 651.5 (M + H)

163 Ethyl 2-[(3S,4R)-4-{[(3,4- dichloro-5-methyl-1H- ¹H NMR (¹H NMR (400MHz, Example pyrrol-2- DMSO-d₆): δ 0.91 (d, 3H), 143 andyl)carbonyl]amino}-3- 1.21 (t, 3H), 1.46 (m, 2H), 1.78 4-tetra-methylpiperidin-1-yl]-4-{5- (m, 4H), 1.91 (m, 2H), 2.17 (s, hydro-[4-(tetrahydrofuran-2- 4H), 2.47 (m, 2H), 2.50 (m, furan-ylmethyl)piperazin-1- 1H), 2.60 (m, 2H), 3.44 (m, 2meth-yl]pyrazin-2-yl}-1,3- 1H), 3.61 (m, 6H), 3.72 (m, ylpiper-thiazole-5-carboxylate 2H), 3.94 (m, 1H), 4.09 (q, azine

2H), 4.24 (m, 1H), 7.20 (d, 1H), 8.30 (d, 2H), 12.03 (s, 1H). LC-MS: m/z691.4 (M + H)

Examples 164-183

The following Examples were prepared according to the proceduredescribed for Example 61 from the starting materials in the table.

Ex Compound Data SM 164 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.92 (d, 3H), 1.22 (m, ample pyrrol-2- 5H),1.81 (m, 2H), 2.15 (m, 144 yl)carbonyl]amino}-3- 4H), 3.03 (m, 4H), 3.80(m, methylpiperidin-1-yl]-4-[5- 6H), 4.12 (d, 1H), 4.28 (m,(4-ethylpiperazin-1- 1H), 4.42 (m, 2H), 7.59 (s, yl)pyrazin-2-yl]-1,3-1H), 8.52 (s, 1H), 9.03 (s, 1H), thiazole-5-carboxylic acid 11.42 (s,1H), 12.60 (m, 1H).

LC-MS: m/z 607.5 (M + H) 165 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO-Ex- dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.64 (m, ample pyrrol-2-6H), 1.82 (m, 2H), 2.19 (s, 145 yl)carbonyl]amino}-3- 3H), 3.63 (m,10H), 4.26 (m, methylpiperidin-1-yl]-4-[5- 1H), 7.20 (d, 1H), 8.41 (s,1H), (piperidin-1-yl)pyrazin-2- 8.99 (s, 1H), 12.04 (s, 1H).yl]-1,3-thiazole-5-carboxylic LC-MS: m/z 578 (M + H) acid

166 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.84 (t, ample pyrrol-2- 2H),2.19 (s, 4H), 3.54 (m, 146 yl)carbonyl]amino}-3- 3H), 3.72 (m, 10H),4.26 (t, methylpiperidin-1-yl]-4-[5- 1H), 7.20 (d, 1H), 8.43 (s, 1H),(morpholin-4-yl)pyrazin-2- 9.02 (s, 1H), 12.04 (s, 1H).yl]-1,3-thiazole-5-carboxylic LC-MS: m/z 580.2 (M + H) acid

167 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.82 (m, ample pyrrol-2- 2H),2.19 (s, 4H), 2.70 (s, 3H), 147 yl)carbonyl]amino}-3- 3.10 (s, 3H), 3.60(m, 7H), methylpiperidin-1-yl]-4-[5- 4.24 (s, 1H), 4.37 (m, 2H),(4-methylpiperazin-1- 7.27 (d, 1H), 8.52 (s, 1H), 9.03yl)pyrazin-2-yl]-1,3- (s, 1H), 10.35 (s, 1H), 12.15 (s,thiazole-5-carboxylic acid 1H).

LC-MS: m/z 593.3 (M + H) 168 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO-Ex- dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.82 (m, ample pyrrol-2-2H), 2.19 (s, 4H), 3.17 (m, 148 yl)carbonyl]amino}-3- 4H), 3.62 (m, 5H),3.78 (s, methylpiperidin-1-yl]-4-[5- 1H), 3.9 (s, 4H), 4.27 (s, 1H),(piperazin-1-yl)pyrazin-2- 7.37 (d, 1H), 8.49 (s, 1H), 9.02yl]-1,3-thiazole-5-carboxylic (s, 1H), 12.28 (s, 1H) acid LC-MS: m/z579.3 (M + H)

169 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.88 (m, ample pyrrol-2- 5H),2.16 (m, 6H), 3.41 (m, 149 yl)carbonyl]amino}-3- 5H), 3.56 (m, 6H), 4.26(s, methylpiperidin-1-yl]-4-(5- 1H), 7.26 (d, 1H), 8.03 (s, 1H),{[2-(2-oxopyrrolidin-1- 8.95 (s, 1H), 12.12 (s, 1H).yl)ethyl]amino}pyrazin-2- LC-MS: m/z 621.3 (M + H)yl)-1,3-thiazole-5-carboxylic acid

170 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.81 (m, ample pyrrol-2- 2H),2.07 (s, 3H), 2.19 (s, 4H), 150 yl)carbonyl]amino}-3- 3.28 (s, 3H) 3.68(m, 6H), 4.26 methylpiperidin-1-yl]-4-{5- (s, 1H), 7.27 (d, 1H), 7.99(s, [(2- 1H), 8.04 (s, 1H), 8.92 (s, 1H), methoxyethyl)amino]pyrazin-12.14 (s, 1H) 2-yl}-1,3-thiazole-5- LC-MS: m/z 568.4 (M + H) carboxylicacid

171 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.82 (m, ample pyrrol-2- 2H),2.19 (s, 4H), 3.13 (m, 151 yl)carbonyl]amino}-3- 4H), 3.64 (m, 11H),3.97 (s, methylpiperidin-1-yl]-4-(5- 2H) 4.27 (s, 1H), 8.06 (s, 1H),{[2-(morpholin-4- 8.20 (s, 1H), 8.96 (s, 1H), yl)ethyl]amino}pyrazin-2-12.17 (s, 1H). yl)-1,3-thiazole-5-carboxylic LC-MS: m/z 623.5 (M + H)acid

172 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.82 (m, ample pyrrol-2- 2H),2.19 (m, 4H), 3.32 (m, 152 yl)carbonyl]amino}-3- 6H), 3.65 (m, 8H), 4.34(m, methylpiperidin-1-yl]-4-{5- 2H), 7.21 (d, 1H), 7.96 (d, 1H),[(1,3-dimethoxypropan-2- 8.02 (s, 1H), 8.95 (s, 1H),yl)amino]pyrazin-2-yl}-1,3- 12.04 (s, 1H). thiazole-5-carboxylic acidLC-MS: m/z 612.48 (M + H)

173 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (m, 3H), 1.82 (s, ample pyrrol-2- 2H),2.19 (s, 4H), 3.23 (m, 153 yl)carbonyl]amino}-3- 4H), 3.49 (m, 2H), 3.53(m, methylpiperidin-1-yl]-4-(5- 6H), 4.26 (s, 1H), 6.30 (s, 1H),{[2-(2-oxoimidazolidin-1- 7.31 (d, 1H), 7.97 (s, 1H), 8.02yl)ethyl]amino}pyrazin-2- (s, 1H), 8.94 (s, 1H), 12.19 (s,yl)-1,3-thiazole-5-carboxylic 1H) acid LC-MS: m/z 622.3 (M + H)

174 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 181 (m, ample pyrrol-2- 2H),2.07 (s, 3H), 2.19 (s, 6H), 154 yl)carbonyl]amino}-3- 2.79 (s, 4H), 3.26(m, 2H), methylpiperidin-1-yl]-4-(5- 3.66 (m, 3H), 4.27 (s, 1H), {[2-7.44 (d, 1H), 8.06 (s, 1H), 8.27 (dimethylamino)ethyl]amino} (s, 1H),8.96 (s, 1H), 12.37 (s, pyrazin-2-yl)-1,3-thiazole- 1H), 16.49 (s, 1H)5-carboxylic acid LC-MS: m/z 581.2 (M + H)

175 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.82 (m, ample pyrrol-2- 2H),2.19 (m, 4H), 2.41-2.98 155 yl)carbonyl]amino}-3- (m, 13H), 3.58 (m,7H), 4.27 methylpiperidin-1-yl]-4-(5- (m, 1H), 7.38 (br s, 1H), 7.96{[2-(4-methylpiperazin-1- (br s, 1H), 8.01 (s, 1H), 8.94yl)ethyl]amino}pyrazin-2- (s, 1H), 12.28 (brs, 1H).yl)-1,3-thiazole-5-carboxylic LC-MS: m/z 636.47 (M + H) acid

176 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (m, 9H), 1.82 (m, ample pyrrol-2- 2H),2.19 (s, 6H), 2.99 (m, 156 yl)carbonyl]amino}-3- 4H), 3.65 (m, 8H), 4.27(s, methylpiperidin-1-yl]-4-{5- 1H), 4.52 (s, 1H), 7.34 (s, 1H), [4-(2-8.51 (s, 1H), 9.02 (s, 1H), methylpropyl)piperazin-1- 10.18 (s, 1H),12.24 (s, 1H). yl]pyrazin-2-yl}-1,3- LC-MS: m/z 637.4 (M + H)thiazole-5-carboxylic acid

177 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.10 (m, ample pyrrol-2- 2H),1.76 (m, 5H), 2.19 (m, 157 yl)carbonyl]amino}-3- 4H), 2.73 (m, 5H), 3.14(m, methylpiperidin-1-yl]-4-(5- 5H), 3.63 (m, 9H), 4.28 (brs,{4-[(1-methylpiperidin-3- 1H), 4.57 (brs, 1H), 7.38 (d,yl)methyl]piperazin-1- 1H), 8.56 (s, 1H), 9.05 (s, 1H),yl}pyrazin-2-yl)-1,3- 10.27 (brs, 1H), 11.09 (brs, thiazole-5-carboxylicacid 1H), 12.27 (s, 1H).

LC-MS: m/z 691.70 (M + H) 178 4-{5-[4- ¹H NMR (400 MHz, DMSO- Ex-(cyclohexylmethyl)piperazin- d₆): δ 0.94 (m, 5H), 1.19 (m, ample1-yl]pyrazin-2-yl}-2- 4H), 1.68 (m, 7H), 1.81 (s, 158[(3S,4R)-4-{[(3,4-dichloro- 4H), 2.19 (s, 4H), 2.97 (m,5-methyl-1H-pyrrol-2- 2H), 3.10 (m, 2H), 3.61 (m, yl)carbonyl]amino}-3-4H), 4.27 (s, 1H), 4.53 (d, 2H), methylpiperidin-1-yl]-1,3- 7.33 (s,1H), 8.55 (s, 1H), 9.04 thiazole-5-carboxylic acid (s, 1H), 12.21 (s,1H), 16.42 (s,

1H). LC-MS: m/z 675.5 (M + H) 179 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Ex- dichloro-5-methyl-1H- d₆): δ 0.88 (m, 9H), 1.27 (d, amplepyrrol-2- 2H), 1.43 (d, 2H), 1.81 (m, 159 yl)carbonyl]amino}-3- 2H),2.17 (s, 5H), 2.56 (s, 3H), methylpiperidin-1-yl]-4-{5- 3.29 (s, 3H),3.58 (m, 7H), [4-(pentan-3-yl)piperazin-1- 4.24 (s, 1H), 7.18 (d, 1H),8.39 yl]pyrazin-2-yl}-1,3- (s, 1H), 8.98 (s, 1H) 12.03 (s,thiazole-5-carboxylic acid 1H).

LC-MS: m/z 649.5 (M + H) 180 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO-Ex- dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H), 1.18 (m, ample pyrrol-2-6H), 1.81 (m, 2H), 2.19 (m, 160 yl)carbonyl]amino}-3- 4H), 2.50 (m, 6H),3.01 (m, methylpiperidin-1-yl]-4-(5- 6H), 3.73 (m, 8H), 4.28 (brs,{4-[2- 1H), 7.50 (brs, 1H), 8.53 (s, (diethylamino)ethyl]piperazin- 1H),9.01 (s, 1H), 12.45 (s, 1-yl}pyrazin-2-yl)-1,3- 1H).thiazole-5-carboxylic acid LC-MS: m/z 706.76 (M + H)

181 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.91 (d, 3H), 1.29 (d, ample pyrrol-2- 3H),1.80 (m, 2H), 2.17 (s, 161 yl)carbonyl]amino}-3- 4H), 3.17 (m, 5H), 3.59(m, methylpiperidin-1-yl]-4-{5- 3H), 3.77 (m, 1H), 4.26 (s,[(3R)-3-methylpiperazin-1- 1H), 4.48 (d, 2H), 7.43 (d, 1H),yl]pyrazin-2-yl}-1,3- 8.52 (s, 1H), 9.01 (s, 1H), 9.43thiazole-5-carboxylic acid (s, 1H), 9.54 (s, 1H), 12.37 (s,

1H). LC-MS: m/z 593.4 (M + H) 182 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Ex- dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H), 1.82 (m, amplepyrrol-2- 2H), 2.19 (s, 4H), 3.21 (m, 162 yl)carbonyl]amino}-3- 4H),3.62 (m, 10H), 4.27 (s, methylpiperidin-1-yl]-4-{5- 1H), 4.56 (brs, 2H),5.39 (s, [4-(2- 1H), 7.33 (d, 1H) 8.53 (s, 1H),hydroxyethyl)piperazin-1- 9.04 (s, 1H), 10.29 (s, 1H),yl]pyrazin-2-yl}-1,3- 12.22 (s, 1H). thiazole-5-carboxylic acid LC-MS:m/z 623.26 (M + H)

183 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Ex-dichloro-5-methyl-1H- d₆): δ 0.94 (d, 3H) 1.23 (m, ample pyrrol-2- 2H),1.50 (m, 2H), 1.82 (m, 163 yl)carbonyl]amino}-3- 5H), 1.99 (m, 12H),2.18 (s, methylpiperidin-1-yl]-4-{5- 4H), 2.93 (m, 5H), 3.76 (m,[4-(tetrahydrofuran-2- 7H), 4.12 (s, 1H), 4.27 (s, 1H),ylmethyl)piperazin-1- 7.28 (d, 1H), 8.47 (s, 1H), 9.02yl]pyrazin-2-yl}-1,3- (s, 1H), 12.17 (s, 1H). thiazole-5-carboxylic acidLC-MS: m/z 663.3 (M + H)

Example 184

Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate

To a stirred solution of methyl2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate(Intermediate 67, 30 mg, 0.08 mmol) in N-methylpyrrolidinone (0.5 mL),N,N-diisopropyl ethylamine (23 mg, 0.18 mmol) and3,4-dichloro-N-[(3S,4R)-3-methoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide(WO2006087543, 27 mg, 0.09 mol) were added at room temperature. Theabove reaction mixture was heated at 90° C. for 3 h. The reactionmixture was cooled to room temperature, diluted with water (5 mL) andstirred for 1 h. The solid obtained was collected by filtration anddried to obtain methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate35 mg (66%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.51 (bs, 4H), 1.63 (s, 2H), 2.18 (s, 3H),2.41 (m, 2H), 2.96 (m, 1H), 3.38 (s, 3H), 3.57 (m, 2H), 3.95 (m, 1H),4.28 (m, 2H), 6.79 (d, 1H), 7.16 (d, 1H), 8.18 (d, 1H), 12.12 (br s,1H).

LC-MS: m/z 608.45 (M+H).

Examples 185-188

The following Examples were prepared according to the proceduredescribed for Example 184 from the starting materials indicated in thetable.

Ex Compound Data SM 185 Methyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz,DMSO- Intermediate 68 dichloro-5-methyl-1H- d₆): δ 0.93 (d, 2H), 1.75(bs, pyrrol-2- 2H), 2.18 (s, 3H), 3.37 (s, 3H), yl)carbonyl]amino}-3-3.57 (m, 9H), 4.01 (m, 2H), methoxypiperidin-1-yl]-4- 4.27 (m, 2H), 6.83(d, 1H), [4-(morpholin-4- 7.17 (d, 1H), 8.25 (d, 1H),yl)pyrimidin-2-yl]-1,3- 12.16 (bs, 1H) thiazole-5-carboxylate LC-MS: m/z610.3 (M + H)

186 methyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Intermediate 69dichloro-5-methyl-1H- d₆): δ 1.09 (t, 2H), 1.75 (m, pyrrol-2- 2H), 2.18(m, 6H), 2.34 (m, yl)carbonyl]amino}-3- 4H), 3.38 (m, 4H), 3.57 (m,methoxypiperidin-1-yl]-4- 7H), 4.10 (m, 1H), 4.27 (m,[4-(4-methylpiperazin-1- 2H), 6.81 (d, 1H), 7.15 (d, 1H),yl)pyrimidin-2-yl]-1,3- 8.21 (d, 1H), 12.10 (bs, 1H).thiazole-5-carboxylate LC-MS: m/z 623.44 (M + H)

187 Methyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Intermediate 70dichloro-5-methyl-1H- d₆): δ 0.86 (d, 6H), 0.97 (m, pyrrol-2- 1H), 1.23(m, 3H), 1.77 (m, yl)carbonyl]amino}-3- 3H), 2.05 (d, 2H), 2.18 (s, 3H),methoxypiperidin-1-yl]-4- 2.37 (m, 4H), 3.38 (s, 3H), {4-[4-(2- 3.57 (m,6H), 4.01 (m, 2H), methylpropyl)piperazin-1- 4.25 (m, 1H), 6.79 (d, 1H),yl]pyrimidin-2-yl}-1,3- 7.17 (d, 1H), 8.20 (d, 1H),thiazole-5-carboxylate 12.18 (bs, 2H)

LC-MS: m/z 665.44 (M + H) 188 Methyl 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400MHz, DMSO- Intermediate 71 dichloro-5-methyl-1H- d₆): δ 0.93 (d, 3H),1.02 (t, pyrrol-2- 3H), 1.75 (m, 2H), 2.18 (s, yl)carbonyl]amino}-3-3H), 2.40 (m, 6H), 3.38 (s, methoxypiperidin-1-yl]-4- 3H), 3.57 (m, 7H),4.01 (m, [4-(4-ethylpiperazin-1- 1H), 4.25 (m, 2H), 6.82 (d,yl)pyrimidin-2-yl]-1,3- 1H), 7.15 (d, 1H), 8.21 (d, 1H),thiazole-5-carboxylate 12.15 (bs, 1H).

LC-MS: m/z 637.4 (M + H).

Example 1892-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylicacid

To a stirred solution of methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate(Example 184, 35 mg. 0.06 mmol) in tetrahydrofuran (5 mL) was added asolution of lithium hydroxide (9.6 mg, 0.23 mmol) in water (1 mL). Thereaction mixture was stirred at room temperature for 18 h. The reactionmixture was concentrated to dryness. The resulting residue was dilutedwith water (2 mL) and the aqueous layer was extracted with diethyl ether(2×10 mL). The aqueous layer was acidified to pH 4-5 with 2N HClsolution, solid obtained was filtered and dried to yield2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylicacid 27 mg (79%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.51-1-82 (m, 7H), 2.18 (s, 3H), 3.18-3.84(m, 12H), 4.25 (m, 1H), 4.55 (m, 1H), 6.99 (d, 1H), 7.16 (d, 1H), 8.31(d, 1H), 12.15 (bs, 1H).

D₂O: 1.66 (m, 7H), 2.18 (s, 3H), 3.41 (m, 4H), 3.59 (m, 4H), 3.85 (m,5H), 4.42 (m, 1H), 4.52 (m, 1H), 6.95 (d, 1H), 8.28 (d, 1H)

LC-MS: m/z 594.40 (M+H).

Examples 190-193

The following Examples were prepared according to the proceduredescribed for Example 189 from the starting material indicated in thetable.

Ex Compound Data SM 190 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO-Example 185 dichloro-5-methyl-1H- d₆): δ 1.76 (m, 2H), 2.18 (s,pyrrol-2- 3H), 3.37 (m, 5H), 3.56 (m, yl)carbonyl]amino}-3- 1H), 3.81(m, 9H), 4.26 (m, methoxypiperidin-1-yl]-4- 1H), 4.41 (m, 1H), 7.05 (d,[4-(morpholin-4- 1H), 7.20 (d, 1H), 8.40 (d, 1H),yl)pyrimidin-2-yl]-1,3- 12.20 (s, 1H). thiazole-5-carboxylic acid LC-MS:m/z 596.4 (M + H)

191 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Example 186dichloro-5-methyl-1H- d₆): δ 1.77 (m, 2H), 2.19 (s, pyrrol-2- 3H), 2.84(s, 3H), 3.22 (m, yl)carbonyl]amino}-3- 2H), 3.41 (m, 7H), 3.91 (m,methoxypiperidin-1-yl]-4- 2H), 4.24 (m, 2H), 4.68 (m,[4-(4-methylpiperazin-1- 4H), 7.07 (d, 1H), 8.44 (d, 1H),yl)pyrimidin-2-yl]-1,3- LC-MS: m/z 609.40 (M + H). thiazole-5-carboxylicacid

192 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Example 187dichloro-5-methyl-1H- d₆): δ 1.00 (d, 6H), 2.12 (m, pyrrol-2- 1H), 2.18(s, 3H), 3.08 (m, yl)carbonyl]amino}-3- 5H), 3.34 (m, 4H), 3.59 (m,methoxypiperidin-1-yl]-4- 7H), 3.95 (m, 1H), 4.29 (m, {4-[4-(2- 1H),4.50 (m, 1H).7.10 (d, methylpropyl)piperazin-1- 1H), 7.21 (d, 1H), 8.49(d, 1H), yl]pyrimidin-2-yl}-1,3- 10.38 (bs, 1H), 12.22 (s, 1H)thiazole-5-carboxylic acid LC-MS: m/z 651.46 (M + H).

193 2-[(3S,4R)-4-{[(3,4- ¹H NMR (400 MHz, DMSO- Example 188dichloro-5-methyl-1H- d₆): δ 1.28 (t, 3H), 1.77 (m, pyrrol-2- 2H), 2.18(s, 3H), 3.08 (m, yl)carbonyl]amino}-3- 4H), 3.21-3.62 (m, 10H), 3.92methoxypiperidin-1-yl]-4- (m, 1H), 4.27 (m, 1H), 4.51[4-(4-ethylpiperazin-1- (m, 3H), 7.11 (m, 2H), 8.49 (d,yl)pyrimidin-2-yl]-1,3- 1H), 10.63 (bs, 1H), 12.20 (s,thiazole-5-carboxylic acid 1H).

LC-MS: m/z 623.35 (M + H).

Example 194

Ethyl4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate

Ethyl4-(5-chloropyrazin-2-yl)-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate(Example 59, 330 mg, 0.57 mmol) was added to a solution of1-(1,4-diazabicyclo[2.2.2]oct-2-yl)methanamine (EP748807, 407 mg, 2.88mmol) and N,N-Diisopropylethylamine (0.38 mL, 2.88 mmol) in N-methyl2-pyrrolidinone (5 mL) and the resulting reaction mixture was stirredfor 20 h at 80° C. The reaction mixture was cooled to room temperature,poured into water (40 mL) and extracted with ethyl acetate (3×50 mL).The combined organic layer was washed with brine, dried over anhydroussodium sulphate and concentrated under reduce pressure to yield crudeproduct which was purified by flash column chromatography over silicagel (0-30% methanol in chloroform) to afford 80 mg (20.5%) of ethyl4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylateas an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.09 (t, 3H), 1.76 (m, 2H), 2.09-2.20 (m,7H), 2.44 (m, 4H), 2.81-2.93 (m, 5H), 2.98-3.01 (m, 4H), 4.25 (m, 2H),4.30 (m, 4H), 7.29 (m, 3H), 7.17 (d, 1H), 8.33 (d, 2H)

LC-MS: m/z 678.48 (M+H).

Example 1954-{5-(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylicacid

Ethyl4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylate(Example 194, 100 mg, 0.14 mmol) was dissolved in methanol (3 mL) andwater (1 mL). Lithium hydroxide monohydrate (18 mg, 0.44 mmol) was addedand the reaction mixture was stirred at room temperature for 16 h. Themethanol was completely evaporated. The resulting crude product wastaken in water (20 mL) and acidified to pH 6 with 2N hydrochloric acid(1.0 mL). The aqueous layer was concentrated to a residue, which waspurified by preparative thin layer chromatography to afford 64 mg(66.8%) of4-{5-[(1,4-diazabicyclo[2.2.2]oct-2-ylmethyl)amino]pyrazin-2-yl}-2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-1,3-thiazole-5-carboxylicacid as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.16-1.23 (m, 3H), 1.77 (m, 2H), 2.09-2.19(m, 5H), 2.19-2.43 (m, 3H), 2.50-2.89 (m, 5H), 3.06 (m, 1H), 3.56 (m,1H), 3.87 (s, 3H), 4.25-4.39 (m, 3H), 7.18 (d, 1H), 8.41 (s, 1H), 8.94(s, 1H)

LC-MS: m/z 650.51 (M+H).

Example 196 Methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate

Methyl2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate(Intermediate 2, 68 mg, 0.267 mmol) was added to a solution of4-chloro-5-methyl-N-[(3R,4S)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide(Intermediate 74, 80 mg, 0.267 mmol) and DIPEA (0.04 mL, 0.8025 mmol) inN-methyl 2-pyrrolidinone (1.0 mL) and the resulting reaction mixture wasstirred overnight at 80° C. The reaction mixture was cooled to roomtemperature and poured into water (30 mL). The solid that formed wascollected by filtration, washed well with diethyl ether (30 mL) anddried to afford methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate80 mg (57.1%) as solid.

¹H NMR (400 MHz, CDCl₃): δ 0.85 (t, 3H), 1.60 (m, 2H), 2.01 (m, 2H),2.28 (s, 3H), 3.31 (m, 4H), 3.68 (m, 2H), 3.74 (s, 3H), 3.85 (s, 3H),4.08 (m, 1H), 4.31 (m, 1H), 6.17 (d, 1H), 7.98 (s, 1H), 9.15 (s, 1H).

LCMS: m/z 522.3 (M+H).

Examples 197-199

The following Examples were prepared according to the proceduredescribed for Example 196 from the starting materials described in thetable.

Ex Compound Data SM 197 Methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.91 (t, 3H), 160 (m, 2H), 2.01 (m, 2H), 2.25(s, 3H), 3.20 (m, 2H), 3.37 (m, 4H), 3.63 (m, 4H), 3.71 (s, 3H), 4.09(s, 3H), 4.28 (m, 1H), 4.34 (m, 1H), 6.19 (d, 1H), 7.15 (2d, 2H), 9.27(s, 1H). LCMS: m/z 565.2 (M + H). Intermediate 74 and Intermediate 1 198Ethyl 2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.86 (t, 3H), 1.16 (t, 3H), 1.59 (m, 2H),2.02 (m, 2H), 2.25 (s, 3H), 3.28 (m, 4H), 4.16 (m, 4H), 4.28 (m, 1H),4.44 (m, 1H), 6.21 (d, 1H), 7.37 (m, 1H), 7.48 (d, 1H), 8.50 (d, 1H),9.29 (s, 1H). LCMS: m/z 550.3 (M + H). Intermediate 74 and Intermediate4 199 Ethyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.85 (t, 3H), 1.02 (m, 2H), 1.22 (t, 3H),2.02 (m, 2H), 2.28 (s, 3H), 3.32 (m, 4H), 3.71 (m, 1H), 4.19 (m, 4H),4.45 (m, 1H), 6.19 (d, 1H), 8.57 (s, 1H), 8.66 (s, 1H), 8.88 (s, 1H),9.08 (s, 1H). Intermediate 74 and Intermediate 3

Example 2002-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid

Methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate(Example 196, 80 mg, 0.153 mmol) was dissolved in methanol (30 mL), and2N sodium hydroxide (6 mL) was added and stirred at room temperature for4 h. The methanol was completely evaporated and water (20 mL) was added.The aqueous layer was washed with diethyl ether (2×20 mL) and theaqueous layer was acidified to pH 3 with 2N hydrochloric acid (2.0 mL).The obtained solid was filtered and dried to afford2-[(3R,4S)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid 60 mg (75%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.73 (t, 3H), 1.39 (m, 2H), 1.97 (m, 2H),2.18 (s, 3H), 3.30 (m, 4H), 3.69 (m, 1H), 4.00 (m, 2H), 4.02 (s, 3H),4.06 (m, 2H), 6.87 (s, 1H), 7.63 (d, 1H), 8.25 (s, 1H), 11.63 (s, 1H).

LCMS: m/z 508.2 (M+H).

Example 201-203

The following Examples were prepared according to the proceduredescribed for Example 200 from the starting materials indicated in thetable.

Ex Compound Data SM 2012-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.72 (t, 3H), 1.41 (m, 2H), 1.97 (m, 2H),2.13 (s, 3H), 3.23 (s, 3H), 3.37 (m, 2H), 3.43 (m, 2H), 3.55 (m, 2H),3.74 (m, 4H), 4.21 (m, 1H), 4.82 (m, 2H), 6.86 (s, 1H), 7.33 (s, 1H),7.50 (s, 1H), 7.65 (d, 1H), 11.64 (s, 1H). LCMS: m/z 551.2 (M + H)Example 197 2022-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.80 (t, 3H), 1.38 (m, 2H), 1.99 (m, 2H),2.18 (s, 3H), 3.29 (m, 2H), 3.45 (m, 2H), 3.65 (m, 1H), 4.03 (m, 1H),4.16 (m, 2H), 6.87 (s, 1H), 7.54 (m, 1H), 7.62 (m, 1H), 7.77 (m, 1H),8.45 (m, 1H), 11.63 (s, 1H), 12.80 (s, 1H). LCMS: m/z 522.2 (M + H)Example 198 2032-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.72 (t, 3H), 1.37 (m, 2H), 2.00 (m, 2H),2.13 (s, 3H), 3.33 (m, 2H), 3.49 (m, 2H), 3.67 (m, 1H), 4.01 (m, 1H),4.19 (m, 2H), 6.86 (s, 1H), 7.62 (d, 1H), 8.78 (m, 1H), 8.83 (m, 1H),9.33 (s, 1H), 11.63 (s, 1H) LCMS: m/z 505.2 (M + H) Example 199

Examples 204-207

The following Examples were prepared according to the proceduredescribed for Example 196 from the starting materials described in thetable.

Ex Compound Data SM 204 Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO- d₆): δ 0.76 (t, 3H), 1.45 (m, 2H), 1.88 (m, 2H),2.17 (s, 3H), 3.48 (m, 4H), 3.45 (m, 1H), 3.65 (s, 3H), 3.72 (s, 3H),4.25 (m, 3H), 7.54 (d, 1H), 8.01 (s, 1H). LC-MS: m/z 547.3 (M + H)Intermediate 76 and Intermediate 2 205 Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO- d₆): δ 0.76 (t, 3H), 1.45 (m, 2H), 1.88 (m, 2H),2.17 (s, 3H), 3.17 (s, 3H), 3.38 ( (m, 6H), 3.50 (m, 2H), 3.61 (s, 3H),3.67 (m, 1H), 4.00 (m, 2H), 4.23 (m, 1H), 6.94 (s, 1H), 7.25 (s, 1H),7.56 (d, 1H). LC-MS: m/z 590.4 (M + H) Intermediate 76 and Intermediate1 206 Ethyl 2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO- d₆): δ 0.73 (t, 3H), 1.03 (t, 3H), 1.44 (m, 2H),1.92 (m, 2H), 2.17 (s, 3H), 3.33 (m, 4H), 3.66 (m, 1H), 3.95 (m, 1H),4.05 (m, 2H), 4.22 (m, 2H), 7.55 (m, 2H), 7.81 (m, 1H), 8.47 (d, 1H),12.69 (s, 1H). LC-MS: m/z 575.4 (M + H) Intermediate 76 and Intermediate4 207 Ethyl 2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate

1H NMR (400 MHz, DMSO- d₆): δ 0.76 (t, 3H), 1.08 (t, 3H), 1.45 (m, 2H),1.90 (m, 2H), 2.19 (s, 3H), 3.30 (m, 4H), 3.67 (m, 1H), 3.98 (m, 1H),4.10 (m, 2H), 4.23 (m, 2H), 7.56 (d, 1H), 8.67 (s, 1H), 8.70 (s, 1H),8.82 (s, 1H), 12.72 (s, 1H). LC-MS: m/z 558.4 (M + H) Intermediate 76and Intermediate 3

Example 208-211

The following Examples were prepared according to the proceduredescribed for Example 200 from the starting materials indicated in thetable.

Ex Compound Data SM 2082-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.72 (t, 3H), 1.41 (m, 2H), 1.97 (m, 2H),2.13 (s, 3H), 3.23 (s, 3H), 3.37 (m, 2H), 3.43 (m, 2H), 3.55 (m, 2H),3.74 (m, 4H), 4.21 (m, 1H), 4.82 (m, 2H), 6.86 (s, 1H), 7.33 (s, 1H),7.50 (s, 1H), 7.65 (d, 1H), 11.64 (s, 1H). LCMS: m/z 551.2 (M + H)Example 204 209 2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.71 (t, 3H), 1.45 (m, 2H), 1.91 (m, 2h),1.92 (s, 3H), 3.23 (s, 3H), 3.42 (m, 4H), 3.71 (m, 2H), 3.72 (m, 1H),3.95 (m, 1H), 4.27 (m, 2H), 4.82 (m, 2H), 7.34 (s, 1H), 7.51 (s, 1H),7.60 (d, 1H), 12.70 (s, 1H). LC-MS: m/z 576.3 (M + H). Example 205 2102-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.70 (t, 3H), 1.41 (m, 2H), 1.90 (m, 2H),2.20 (s, 3H), 3.38 (m, 4H), 3.70 (m, 1H), 4.02 (m, 1H), 4.29 (m, 2H),7.70 (d, 1H), 8.78 (s, 1H), 8.84 (s, 1H), 9.35 (s, 1H), 12.90 (s, 1H),15.30 (s, 1H). (LC-MS: m/z 547.3 (M + H) Example 206 2112-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.72 (t, 3H), 1.43 (m, 2H), 1.90 (m, 2H),2.20 (s, 3H), 3.37 (m, 2H), 3.47 (m, 2H), 3.67 (m, 1H), 3.95 (m, 1H),4.24 (m, 2H), 7.54 (m, 1H), 7.61 (d, 1H), 7.77 (m, 1H), 8.45 (s, 1H),12.75 (s, 1H) (LC-MS: m/z 530.3 (M + H). Example 207

Examples 212-214

The following Examples were prepared according to the proceduredescribed for Example 196 from the starting materials indicated in thetable.

Ex Compound Data SM 212 Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.86 (t, 3H), 1.55 (m, 2H), 2.06 (m, 2H),2.27 (s, 3H), 3.34 (m, 4H), 3.73 (s, 3H), 3.84 (t, 3H), 4.05 (m, 1H),4.29 (m, 1H) 4.31 (m, 2H), 7.26 (d, 1H), 7.97 (s, 1H), 9.45 (s, 1H).LCMS: m/z 556.3 (M + H) Intermediate 78 and Intermediate 2 213 Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.84 (t, 3H), 1.02 (m, 2H), 1.16 (t, 3H),2.09 (m, 2H), 2.27 (s, 3H), 3.33 (m, 4H), 3.70 (m, 2H), 4.16 (m, 3H),4.33 (m, 1H), 7.26 (d, 1H), 7.46 (m, 1H), 8.51 (d, 1H), 9.44 (s, 1H).LCMS: m/z 584.3 (M + H) Intermediate 78 and Intermediate 4 214 Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.95 (t, 3H), 1.58 (m, 2H), 1.89 (m, 2H) 2.03(m, 2H), 2.27 (s, 3H), 3.22 (m, 2H), 3.35 (m, 4H), 3.63 (m 4H), 3.71 (s,3H), 4.10 (m, 2H), 4.38 (m, 1H), 7.19 (d, 1H), 7.21 (d, 1H), 7.26 (s,1H), 9.35 (s, 1H). LCMS: m/z 599.3 (M + H) Intermediate 78 andIntermediate 1

Examples 215-217

The following Examples were prepared according to the proceduredescribed for Example 200 from the starting materials indicated in thetable.

Ex Compound Data SM 2152-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.75 (t, 3H), 1.46 (m, 2H), 1.80 (m, 2H),2.18 (s, 3H), 3.29 (s, 3H), 3.39 (m, 2H), 3.67 (m, 1H), 4.05 (m, 1H),4.08 (m, 2H), 4.30 (m, 2H), 7.10 (d, 1H), 8.24 (s, 1H), 12.14 (s, 1H))LCMS: m/z 542.0 (M + H) Example 212 2162-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.77 (t, 3H), 1.47 (m, 2H), 1.81 (m, 2H),2.18 (s, 3H), 3.30 (s, 3H), 3.35 (m, 2H), 3.39 (m, 1H), 3.61 (m, 2H),3.72 (m, 2H), 3.96 (m, 1H), 4.28 (m, 2H), 4.82 (m, 2H), 7.10 (d, 1H),7.33 (s, 1H), 7.50 (s, 1H), 12.15 (s, 1H) LCMS: m/z 585.3 (M + H).Example 214 217 2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylic acid

¹H NMR (400 MHz, DMSO- d₆): δ 0.77 (t, 3H), 1.47 (m, 2H), 1.78 (m, 2H),3.18 (s, 3H), 3.33 (m, 4H), 3.62 (m, 1H), 3.93 (m, 1H), 4.26 (m, 2H),7.09 (d, 1H), 7.52 (m, 1H), 7.76 (t, 1H), 8.44 (m, 1H), 12.14 (s, 1H),12.85 (s, 1H). LCMS: m/z 556.0 (M + H). Example 213

Intermediate 1 Methyl2-chloro-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate

Methyl2-amino-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate(Intermediate 5; 0.55 g, 2.2 mmol) was suspended in glacial acetic acid(20 ml) and concentrated HCl (30 ml). The solution was cooled to 0° C.and to this a solution of sodium nitrite in water (15 ml) was addeddropwise. After stirring at 0° C. for 10 mins, the reaction was slowlywarmed to room temperature and stirred for 1 hour. Once complete byLCMS, a solution of urea (0.25 g) in water (10 ml) was added dropwise.After stirring at room temperature for 30 mins, solvent was removedunder reduced pressure. The residue was partitioned with sat. NaHCO₃(aq) and EtOAc. Extraction with EtOAc (×3), drying with MgSO₄ andconcentrating yielded an orange oil which was used without purification(0.20 g). MS (ES) (M+H)⁺: 302 for C₁₁H₁₂ClN₃O₃S; NMR: 3.34 (s, 3H), 3.62(m, 2H), 3.81 (s, 3H), 4.22 (m, 2H), 7.24 (s, 2H).

Intermediates 2-4

The following Intermediates were synthesized by an analogous method toIntermediate WW from the starting materials (SM) given in the tablebelow.

Int Compound Data SM 2 Methyl 2-chloro-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3- thiazole-5-carboxylate

MS (ES) (M + H)⁺: 259 for C₈H₇ClN₄O₂S NMR: 3.92 (s, 6H), 8.04 (s, 1H).Intermediate 6 3 Ethyl 2-chloro-4-pyrazin-2-yl-1,3-thiazole-5-carboxylate

MS (ES) (M + H)⁺: 270 for C₁₀H₈ClN₃O₂S NMR: 1.16 (t, 3H), 4.22 (q, 2H),8.76 (m, 2H), 9.03 (s, 1H) Intermediate 7 4 Ethyl2-chloro-4-(3-fluoropyridin- 2-yl)-1,3-thiazole-5-carboxylate

MS (ES): 287 (MH⁺) for C₁₁H₈ClFN₂O₂S ¹H-NMR (CDCl₃) δ: 1.25 (t, 3H);4.28 (q, 2H); 7.55 (dd, 1H); 7.62 (t, 1H); 8.62 (d, 1H). Intermediate 8

Intermediate 5 Methyl2-amino-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate

N-Iodosuccinimide (9.3 g, 41 mmol) was added to a mixture of 7.52 g (41mmol) methyl 3-(1-methyl-1H-imidazol-2-yl)-3-oxopropanoate (Intermediate10) and 7.5 g Amberlyst-15 resin in 400 ml EtOAc followed by stirringfor 1 hour at room temperature. The resin was filtered off and rinsedwith EtOAc. Solvent was removed from the filtrate and the residue wastaken up in diethyl ether. Insoluble material was filtered off andrinsed with additional ether. Solvent was removed from the filtrate andthe residue was dissolved in 200 ml MeOH before added 4.7 g (62 mmol)thiourea. The mixture was heated at reflux for 1 hour. Solvent wasremoved and the residue was taken up in aqueous Na₂CO₃. Insolublematerial was collected by filtration and rinsed well with water. Thesolids were dried in vacuo affording 4.51 g of product: MS (ES) (M+H)⁺:283 for C₁₁H₁₄N₄O₃S

NMR: 3.22 (s, 3H), 3.61 (m, 2H), 3.69 (s, 3H), 4.32 (m, 2H), 7.91 (s,2H), 8.41 (s, 2H).

Intermediates 6-8

The following Intermediates were synthesized by an analogous method toIntermediate 5 from the starting materials (SM) given in the tablebelow.

Int Compound Data SM 6 Methyl 2-amino-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3- thiazole-5-carboxylate

MS (ES) (M + H)⁺: 240 for C₈H₉N₅O₂S NMR: 3.61 (s, 3H), 3.71 (s, 3H),7.96 (s, 1H), 8.10 (s, 2H). Intermediate 9 7 Ethyl2-amino-4-pyrazin-2-yl- 1,3-thiazole-5-carboxylate

MS (ES) (M + H)⁺: 251 for C₁₀H₁₀N₄O₂S NMR: 1.07 (t, 3H), 4.04 (q, 2H),7.99 (s, 2H), 8.65 (d, 1H), 8.69 (d, 1H), 8.81 (s, 1H) Intermediate 11 8Ethyl 2-amino-4-(3-fluoropyridin- 2-yl)-1,3-thiazole-5-carboxylate

MS (ES): 268 (MH⁺) for C₁₁H₁₀FN₃O₂S ¹H-NMR (DMSO-D6) δ: 1.01 (t, 3H);3.99 (q, 2H); 7.53 (dd, 1H); 7.77 (t, 1H); 7.95 (s, 2H); 8.44 (d, 1H).Intermediate 12

Intermediate 9 Methyl 3-(1-methyl-1H-1,2,4-triazol-5-yl)-3-oxopropanoate

NaH (7.84 g, 196 mmol of a 60% dispersion in oil) was added portion-wiseto a solution of 6.18 g (34.5 mmol) of1-(1-methyl-1H-1,2,4-triazol-5-yl)ethanone (Ohta, S.; Kawasaki, I.;Fukuno, A.; Yamashita, M.; Tada, T.; Kawabata, T. Chem. Pharm. Bull.(1993), 41(7), 1226-31) in 100 ml dimethylcarbonate. The mixture washeated to 90° C. for 2 hour forming a thick slurry. After cooling toroom temperature, the mixture was slowly transferred to 1N HCl over ice.The pH of the mixture was brought to about 7 with NaHCO₃ before beingsaturated with NaCl and extracted 4 times with EtOAc. The EtOAc wasdried (MgSO₄) and concentrated to give an oil that was chromatographedon silica gel (100% DCM followed by gradient elution to 50% EtOAc inDCM). Product (5.3 g) was obtained as an oil. NMR: 3.78 (s, 3H), 4.11(s, 2H), 4.22 (s, 3H), 7.94 (s, 1H).

Intermediates 10-12

The following Intermediates were synthesized by an analogous method toIntermediate 9 from the starting materials (SM) given in the tablebelow.

Int Compound Data SM 10 Methyl 3-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-3-oxopropanoate

MS (ES) (M + H)⁺: 227 for C₁₀H₁₄N₂O₄ NMR: 3.18 (s, 3H), 3.61 (m, 5H),4.07 (s, 2H), 4.52 (m, 2H), 7.24 (s, 1H), 7.61 (s, 1H Intermediate 13 11Ethyl 3-oxo-3-pyrazin-2- ylpropanoate

MS (ES) (M + H)⁺: 195 for C₉H₁₀N₂O₃ NMR: 1.15 (t, 3H), 4.11 (q, 2H),4.18 (s, 2H), 8.82 (s, 1H), 8.94 (s, 1H), 9.17 (s, 1H) pyrazine-2-carboxylic acid 12 Ethyl 3-(3-fluoropyridin-2-yl)-3- oxopropanoate

MS (ES): 212 (MH⁺) for C₁₀H₁₀FNO₃ ¹H-NMR (DMSO-D6) δ: 1.15 (t, 3H); 3.99(q, 2H); 4.10 (s, 2H); 7.45 (dd, 1H); 8.36 (t, 1H); 8.56 (d, 1H).3-fluoropyridine carboxylic acid

Intermediate 13 1-[1-(2-Methoxyethyl)-1H-imidazol-2-yl]ethanone

A solution of 30 ml (75 mmol) of 2.5 M n-butyllithium in hexanes wasadded slowly to a solution of 8.48 g (61.3 mmol)1-(2-Methoxyethyl)-1H-imidazole (WO 2003055876 A1 in 200 ml THF cooledin a dry ice-acetone bath. After stirring 1 hour, 8 ml (75 mmol) ofN-methoxy-N-methylacetamide was added quickly, and the solution wasallowed to warm to room temperature over 30 min. After quenching withaqueous NH₄Cl, the mixture was diluted with water and extracted twicewith EtOAc, which was washed with brine, dried (MgSO₄) and concentratedto give an oil that was chromatographed on silica gel (100% DCM followedby gradient elution to 50% EtOAc in DCM). Product (8.5 g) was obtainedas a mobile oil. MS (ES) (M+H)⁺: 169 for C₈H₁₂CN₂O₂

NMR: 2.69 (s, 3H), 3.34 (s, 3H), 3.71 (m, 2H), 4.61 (m, 2H), 7.12 (s,1H), 7.26 (s, 1H).

Intermediate 14 Ethyl 3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate

Bromine (0.56 ml, 11 mmol) was added to a solution of 1 g (5.3 mmol) ofethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate (WO2006087543) and 0.8ml (5.7 mmol) Et₃N in CH₂Cl₂. After stirring at room temperature for 2h, aqueous NaHSO₃ was added and the CH₂Cl₂ was removed and the aqueousresidue was partitioned between water and EtOAc. The EtOAc layer wasseparated and washed with brine. The EtOAc layer was dried overanhydrous MgSO₄, and the solvent was removed to give 1.5 g of theproduct as a solid. MS (ES) (MH⁺): 240 for C₈H₉BrClNO₂; NMR (d₆-DMSO):1.3 (t, 3H), 2.2 (s, 3H), 4.2 (q, 2H), 12.3 (s, 1H).

Intermediate 15 Ethyl 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate

Nitrogen gas was bubbled through a mixture of 1.4 g (5.25 mmol) of ethyl3-bromo-4-chloro-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 14),470 g (4 mol) Zn(CN)₂, 250 mg (0.26 mmol) Pd₂(dba)₃ and 302 mg (0.26mmol) dppf in 15 ml DMF for 15 min. The mixture was heated at 130° C.for 1 h. Additional Zn(CN)₂ (1 g), Pd₂(dba)₃ (500 mg) and dppf (604 mg)were added. After bubbling through N₂ for 15 min and heating at 130° C.for 2 h, additional Zn(CN)₂ (0.5 g), Pd₂(dba)₃ (250 mg) and dppf (302mg) were added. Heating was continued at 130° C. for 2 h. Solvent wasremoved and the residue was partitioned between EtOAc and water. TheEtOAc was separated and washed with brine. Combined aqueous layers wereextracted again with EtOAc, which was washed with brine. Combined EtOAcextracts were dried (MgSO₄) and concentrated. The residue was purifiedby silica gel chromatography (100% CH₂Cl₂ followed by gradient elutionto 5% MeOH in CH₂Cl₂) to afford 750 mg of product as a solid. MS (ES)(MH⁺): 213 for C₉H₉ClN₂O₂; NMR (d₆-DMSO): 1.3 (t, 3H), 2.2 (s, 3H), 4.3(q, 2H), 13.1 (s, 1H).

Intermediate 16 4-Chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid

A solution of 670 mg (3.2 mmol) of ethyl4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylate (Intermediate 15) and3.2 ml (3.2 mmol) 1N NaOH in 20 ml MeOH was heated at 100° C. in amicrowave reactor for 2 h. The mixture was diluted with water andextracted with EtOAc. The EtOAc was washed with 1N NaOH. The combinedaqueous layers were acidified with concentrated HCl and extracted 2times with EtOAc, each extract being washed with brine. The combinedEtOAc layers were dried over anhydrous MgSO₄, filtered and the solventwas removed to give 535 mg of product as a solid. MS (ES) (M−H): 183 forC₇H₅ClN₂O₂; NMR (d₆-DMSO): 2.2 (s, 3H), 12.9 (s, 1H), 13.3 (s, 1H).

Intermediate 17

Ethyl(3S,4R)-4-[(tert-butoxycarbonyl)amino]-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate

Chiral HPLC purification onCis(±)ethyl-4-[(tert-butoxycarbonyl)amino]-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate(15 g) (WO2006087543) was performed using a Chiralpak AD column andmethanol as the eluent to provide 6.3 g of the title compound. MS(ES)(M+H): 329. for C₁₆H₂₈N₂O₅; NMR□: 1.28 (t, 3H), 1.47 (s, 9H), 1.68(m, 2H), 2.88 (brt, 2H), 3.50 (m, 1H), 3.68 (m, 1H), 3.90 (m, 1H),4.00-4.45 (m, 3H), 4.10 (q, 2H), 4.92 (brs, 1H), 5.20 (m, 2H), 5.86 (m,1H).

Intermediate 18 Ethyl(3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate

Ethyl (3S,4R)-4-[(tert-butoxycarbonyl)amino1-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate (Intermediate 17, 5 g,12.7 mmol) was dissolved in dichloromethane (200 mL) and trifluoroaceticacid (9.79 mL, 127 mmol) was added. The reaction mixture was allowed tostir for 3 h at room temperature. The reaction mixture was basified withsaturated sodium bicarbonate solution (pH ˜8) and the layers wereseparated. The aqueous layer was extracted with dichloromethane; organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure to afford 2.7 g (93.24%). MS (ES) (M+H): 228. forC₁₁H₂₀N₂O₃.

Intermediate 19 Ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate

To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(WO200687543, 2.27 g, 11.8 mmol) and Ethyl(3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate(Intermediate 18, 2.7 g, 11.8 mmol) in dichloromethane (180 mL) wasadded HOBt (1.85 g, 11.8 mM) and N-methylmorpholine (3.8 mL, 35.43mmol). The reaction mixture was stirred for 1 h at room temperature andEDC HCl (4.07 g, 21.3 mmol) was added. The resulting reaction mixturewas stirred for room temperature overnight, treated by the addition of 2N HCl (120 mL) and the resulting layers were evaporated. The organiclayer was washed with sodium bicarbonate (150 mL), water (150 mL) andbrine, dried over anhydrous sodium sulphate, filtered, concentratedunder vacuum. Purification by column chromatography (silica gel, 35%ethylacetate in pet ether) to afforded 3.5 g (73.6%) as brown solid. NMR(400 MHz, DMSO-d₆): δ 1.24 (t, 3H), 1.62 (m, 2H), 2.16 (s, 3H), 2.97 (m,2H), 3.53 (m, 2H), 3.97 (m, 4H), 4.15 (q, 2H), 4.21 (m, 1H), 5.13 (d,1H), 5.23 (d, 1H), 5.87 (m, 1H), 7.10 (d, 1H), 12.10 (s, 1H).

Intermediate 203,4-Dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide

To as solution of Ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate(Intermediate 19, 2.5 g, 6.20 mmol) in toluene (450 mL) was added iodine(6.31 g, 24.8 mmol) followed by hexamethyldisilane (10.34 mL, 49.62 mmoland the reaction mixture was refluxed for 30 h. The reaction mixture wastreated with 10% sodium thiosulphate (300 mL) and layers were separated.The aqueous layer was extracted with toluene and the organic layer wasdried over anhydrous sodium sulphate and concentrated under reducedpressure. Purification by column chromatography (silica, 4% methanol indichloromethane) afforded 750 mg (36.54%) of3,4-dichloro-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide.

LC-MS: m/z 331 (M+H)

¹H NMR (400 MHz, DMSO-d₆): δ 1.57 (m, 2H), 2.16 (s, 3H), 2.56 (s, 1H),2.81 (d, 1H), 3.07 (d, 1H), 3.40 (m, 1H), 3.90 (m, 1H), 4.14 (m, 2H),5.14 (d, 1H), 5.27 (d, 1H), 5.92 (m, 1H), 7.12 (d, 1H).

Intermediate 21 Ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate

To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 16, 562 mg, 3.07 mmol) and ethyl(3S,4R)-4-amino-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate(Intermediate 18, 700 mg, 3.07 mmol) in dichloromethane (150 mL) wereadded HOBt (470 mg, 3.07 mmol) and N-methyl morpholine (1.01 mL, 9.21mmol). The reaction mixture was stirred for 1 h at room temperature andEDC HCl (1.05 g, 5.52 mmol) was added. The resulting reaction mixturewas stirred at room temperature overnight. The reaction mixture wasquenched with the addition of 2 N HCl (100 mL). The organic layer waswashed with sodium bicarbonate (150 mL), water (150 mL) and brine, anddried over anhydrous sodium sulphate, filtered, and concentrated undervacuum. Purification by column chromatography (silica, 35% ethyl acetatein pet ether) afforded Ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate1.1 g (90%) as brown solid.

LC-MS: m/z 395 (M+H).

Intermediate 224-Chloro-3-cyano-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide

To as solution of ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidine-1-carboxylate(Intermediate 21, 1.1 g, 2.79 mmol) in toluene (190 mL) was added iodine(2.9 g, 11.16 mmol) followed by hexamethyldisilane (4.65 mL, 22.33mmol). The reaction mixture was heated to reflux for 30 h and thencooled to room temperature. The reaction mixture was treated 10% sodiumthiosulphate (150 mL) and the layers were separated. The aqueous layerwas extracted with toluene and the organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure.Purification by column chromatography (silica, 4% methanol indichloromethane) afforded 300 mg (33%) of4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-(prop-2-en-1-yloxy)piperidin-4-yl]-1H-pyrrole-2-carboxamide

LC-MS: m/z 323 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.58 (m, 1H), 1.70 (m, 1H), 2.18 (s, 3H),2.69 (m, 3H), 2.93 (d, 1H), 3.17 (d, 1H), 3.33 (m, 1H), 3.52 (br s, 1H),3.97 (m, 1H), 4.10 (m, 2H), 5.11 (d, 1H), 5.31 (d, 1H), 5.90 (m, 1H),7.50 (d, 1H).

Intermediate 23 Ethyl(3S,4R)-4-benzylamino-3-ethoxypiperidine-1-carboxylate

Cis(±)-Ethyl (4-(benzylamino)-3-ethoxypiperidine-1-carboxylate

Chiral HPLC purification on Cis(±)ethyl4-[benzylamino]-3-ethoxypiperidine-1-carboxylate (21 g) (WO2006087543)was performed using a Chiralpak AD column and methanol as the eluent toprovide 11 g of the title compound.

MS (ES) MH⁺: 307 for C₁₇H₂₆N₂O₃; NMR: 1.08 (t, 3H); 1.15 (t, 3H); 1.50(m, 2H); 1.75 (br s, 1H); 2.65 (br s, 1H); 2.92 (m, 2H); 3.47 (br s,1H); 3.55 (m, 1H); 3.71 (m, 3H); 3.88 (br s, 1H); 3.98-4.05 (m, 2H);7.18-7.34 (m 5H)

Intermediate 24 Ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate

Ethyl(3S,4R)-4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate(Intermediate 23, 2.4 g, 6.87 mmol) was dissolved in methanol (150 mL)and hydrogenated over 10% palladium on carbon (1.5 g) under 50 psi ofhydrogen pressure for 2 h at room temperature. The reaction mixture wasthen filtered through a celite bed and the filtrate was concentratedunder reduced pressure to yield 1.33 g (89.62%) of Ethyl(3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate as liquid.

MASS (ES +v): m/z 217 (M+H).

Intermediate 25 Ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate

To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(WO200687543, 1.18 g, 6.15 mmol) and ethyl(3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.33g, 6.15 mmol) in dichloromethane (170 mL) were added HOBT (941 mg, 6.15mmol) and N-methyl morpholine (2.02 mL, 18.45 mmol). The reactionmixture was stirred for 1 h at room temperature and EDC HCl (2.11 g,11.07 mmol) was added. The resulting reaction mixture was stirred forroom temperature overnight. The reaction was quenched with the additionof 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate(150 mL), water (150 mL), and brine, and dried over anhydrous sodiumsulphate, filtered, concentrated under vacuum. Purification by flashcolumn chromatography (silica, 35% ethylacetate in pet ether) affordedethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate1.9 g (49%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.15 (t, 3H), 1.17 (t, 3H), 1.59 (m, 2H),2.15 (s, 3H), 2.94 (m, 2H), 3.37 (t, 1H), 3.46 (m, 1H), 3.97 (m, 1H),6.64 (m, 1H), 4.03 (q, 2H), 4.10 (q, 2H), 7.07 (d, 1H), 12.10 (s, 1H).

LC-MS: m/z 391 (M+H).

Intermediate 26 3,4-Dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide

A solution of ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate(Intermediate 25, 1.9 g, 4.85 mmol), potassium hydroxide (1.9 g, 34.01mmol), and hydrazine hydrate (1.71 mL, 34.01 mmol) in ethylene glycol(150 mL) was stirred for 40 h at 120° C. The reaction mixture was pouredin to water (120 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, concentrated in vacuo to yield the crude product, which wastriturated with water (30 mL) to afford3,4-dichloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide1.0 g (65%) as solid.

LC-MS: m/z 320.11 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (t, 3H), 1.58 (m, 2H), 2.18 (s, 3H),2.55 (s, 1H), 2.84 (d, 1H), 3.06 (d, 1H), 3.39 (m, 4H), 3.63 (m, 1H),4.02 (m, 1H), 4.42 (s, 1H), 7.10 (d, 1H).

Intermediate 27 4-Chloro-5-methyl-1H-pyrrole-2-carboxylic acid

Aqueous lithium hydroxide (2 M, 4 ml) was warmed to 50° C. and asolution of ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate(Intermediate 28, 0.30 g, 1.60 mmol) in MeOH was added to it. Thereaction was heated to 80° C. and stirred for two hours. The MeOH wasremoved and the aqueous solution was cooled to 0° C. and acidified with30% HCl. The precipitated product (0.23 g, 92%) was filtered and dried.MS (ES): 160 (M+1) for C₆H₆ClNO₂; NMR (CDCl₃)□: 2.25 (s, 3H), 6.85 (s,1H), 8.98 (brs, 1H).

Intermediate 28 Ethyl 4-chloro-5-methyl-1H-pyrrole-2-carboxylate

N-Chlorosuccinimide (0.67 g, 5.08 mmol) was added to a solution of ethyl5-methyl-1H-pyrrole-2-carboxylate (Intermediate 29, 0.65 g, 4.23 mmol)in chloroform (20 ml). The reaction was warmed to 40° C. and stirred for4 h, then poured to a beaker containing 2 N NaOH (20 ml) at 0° C. Thelayers were separated and the aqueous layer was extracted withchloroform 3 times. The combined organic extracts were dried overmagnesium sulfate and concentrated. The resultant off-white solid waspurified by flash chromatography (hexanes/EtOAc, 16:1) to give the titleproduct as a white solid (0.3 g, 38%). MS (ES): 188 (M+1) forC₈H₁₀ClNO₂; NMR (CDCl₃)□: 1.34 (t, 3H), 2.27 (s, 3H), 4.30 (q, 2H), 6.76(s, 1H), 9.07 (brs, 1H).

Intermediate 29 Ethyl 5-methyl-1H-pyrrole-2-carboxylate

Sodium (2.79 g, 0.121 mmol) was dissolved in anhydrous EtOH (100 ml),then 2,2,2-trichloro-1-(5-methyl-1H-pyrrol-2-yl)ethanone (Intermediate30, 22.5 g, 0.099 mmol) was added in small portions. The dark brownsolution was stirred at room temperature for 30 min then concentratedunder vacuum to a small volume. The mixture was cooled in an ice bathand 3 N HCl was added slowly, then the mixture was extracted withdiethyl ether (3×100 ml). The ether extracts were washed with 10%NaHCO₃, water and brine, dried over Na₂SO₄ and concentrated in vacuo togive the title compound as a brown solid. (15.04 g). NMR: 1.32 (t, 3H),2.1 (s, 3H), 4.371 (q, 2H), 5.96 (dd, 1H), 6.78 (dd, 1H), 11.67 (s, 1H).

Intermediate 30 2,2,2-Trichloro-1-(5-methyl-1H-pyrrol-2-yl)ethanone

2-Methyl-1H-pyrrole (Intermediate 31, 10 g, 0.123 mmol) in anhydrousdiethyl ether (30 ml) was added dropwise over 1 h to a stirred solutionof trichloroacetyl chloride (29 g, 0.16 mmol) in anhydrous Et₂O (100ml). The mixture was stirred for a further 1 h then K₂CO₃ (10 g/30 ml)was added slowly through a dropping funnel. The organic phase was driedover Na₂SO₄ and treated with decolorizing charcoal (3 g) for 30 min atroom temperature. The resulting purple solution was concentrated andtriturated with n-hexanes to give the title compound as a purple solid.(16.72 g). NMR (CDCl₃): 2.36 (s, 3H), 6.04 (dd, 1H), 7.45 (dd, 1H),10.344 (s, 1H).

Intermediate 31 2-Methyl-1H-pyrrole

Potassium hydroxide (50 g, 0.89 mmol) was added to a solution ofethylene glycol (750 ml) and 1H-pyrrole-2-carbaldehyde (50 g, 0.53mmol). Hydrazine hydrate (37 ml, 0.745 mmol) was added slowly over 15min. The reaction mixture was refluxed at 90° C. for 90 min. The mixturewas cooled to room temperature and cold water (250 ml) was added. Theaqueous mixture was extracted with DCM (250 ml). The organic phase waswashed with water (250 ml), dried over Na₂SO₄ and concentrated in vacuo.Kugelrohr distillation gave the title compound as a clear colorlessliquid (29.75 g). NMR: 2.1 (s, 3H), 5.77 (s, 1H), 5.9 (dd, 1H), 6.25(dd, 1H), 10.54 (s, 1H).

Intermediate 32 Ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate

To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 16, 1.01 g, 5.55 mmol) and ethyl(3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2g, 5.55 mmol) in dichloromethane (480 mL) were added HOBt (850 mg, 5.55mmol) and N-methyl morpholine (1.82 mL, 16.66 mmol). The reactionmixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99mmol) was added. The resulting reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with 2Nhydrochloric acid (120 mL). The organic layer was washed with sodiumbicarbonate (150 mL), water (150 mL) and brine, dried over anhydroussodium sulphate, filtered, concentrated under vacuum. Purification byflash column chromatography (silica, 35% ethylacetate in pet ether)afforded ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate1.5 g (71%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.15 (m, 6H), 1.59 (m, 2H), 2.20 (s, 3H),3.01 (m, 2H), 3.42 (m, 1H), 3.50 (m, 1H), 3.61 (m, 1H), 4.06 (m, 4H),7.46 (d, 1H), 12.69 (s, 1H)

LCMS: m/z 383 (M+H).

Intermediate 334-Chloro-3-cyano-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide

A solution of ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate(Intermediate 32, 1.5 g, 3.92 mmol), potassium hydroxide (1.54 g, 27.48mmol), and hydrazine hydrate (1.38 mL, 27.48 mmol) in ethylene glycol(200 mL) was stirred for 60 h at 120° C. The reaction mixture was pouredin to water (300 mL) and extracted with ethyl acetate (2×300 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, concentrated under vacuum to yield the crude product which wastriturated with water (150 mL) to afford4-chloro-3-cyano-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide(670 mg, 55%) as solid.

LCMS: m/z 311 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.16 (t, 3H), 1.75 (m, 2H), 2.18 (s, 3H),2.78 (m, 2H), 3.01 (d, 1H), 3.21 (d, 1H), 3.46 (m, 2H), 3.54 (m, 1H),3.58 (m, 2H), 4.08 (m, 1H), 7.41 (d, 1H).

Intermediate 34 Ethyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate

To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 27, 0.87 g, 5.55 mol) and ethyl(3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2g, 5.55 mmol) in dichloromethane (150 mL) was added HOBT (850 mg, 0.55mmol) and N-methyl morpholine (1.82 mL, 1.66 mmol). The reaction mixturewas stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol)was added. The resulting reaction mixture was stirred at roomtemperature overnight. The reaction mixture was quenched with theaddition of 2N HCl (120 mL). The organic layer was washed with sodiumbicarbonate (150 mL), water (150 mL) and brine, dried over anhydroussodium sulphate, filtered, concentrated under vacuum. Purification bycolumn chromatography (silica, 35% ethyl acetate in pet ether) affordedEthyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate1.6 g (80%) as brown solid.

LCMS: m/z 358 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 1.11 (t, 3H), 1.20 (t, 3H), 1.46 (d, 1H),1.80 (m, 1H), 2.17 (s, 3H), 2.90 (m, 2H), 3.38 (m, 1H), 3.50 (m, 2H),4.03 (m, 5H), 6.85 (s, 1H), 7.51 (d, 1H), 11.58 (s, 1H).

Intermediate 354-Chloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide

A solution of ethyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate(Intermediate 34, 1.6 g, 4.48 mmol), potassium hydroxide (1.76 g, 31.37mmol), and hydrazine hydrate (1.6 mL, 31.37 mmol) in ethylene glycol(180 mL) was stirred for 40 h at 120° C. The reaction mixture was pouredin to water (120 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, concentrated in vacuo to yield the crude product which wastriturated with water (30 mL) to afford4-chloro-N-[(3S,4R)-3-ethoxypiperidin-4-yl]-5-methyl-1H-pyrrole-2-carboxamide480 mg (37%) as solid.

LCMS: m/z 285 (M+H).

Intermediate 36 Methyl(3S,4R)-4-benzylamino-3-methylpiperidine-1-carboxylate

Chiral HPLC purification onCis(±)methyl-4-benzylamino]-3-methylpiperidine-1-carboxylate (HelveticaChimica Acta, 1969, 52, 629-639, 20 g) was performed using a ChiralpakAD column and methanol as the eluent to provide 9 g of the titlecompound.

¹H NMR (400 MHz, CDCl₃): δ 0.92 (d, 3H), 1.53 (m, 1H), 1.62 (m, 1H),1.80 (br s, 1H), 3.04 (m, 1H), 3.40 (m, 2H), 3.48 (m, 1H), 3.68 (s, 3H).

Intermediate 37 Methyl (3S,4R)-4-amino-3-methylpiperidine-1-carboxylate

Methyl (3S,4R)-4-(benzylamino)-3-methylpiperidine-1-carboxylate (8.0 g,0.02 mol) was dissolved in methanol (200 mL) and hydrogenated at roomtemperature, under 50 psi of hydrogen pressure, in the presence ofpalladium (2.5 g) on carbon for 2 h. The solution was then filtered andconcentrated under reduced pressure to yield 3.5 g (92%) Methyl(3S,4R)-4-amino-3-methylpiperidine-1-carboxylate as liquid.

MASS (APCI): m/z 173.3 (M+H).

¹H NMR (400 MHz, CDCl₃): δ 0.92 (d, 3H), 1.53 (m, 1H), 1.62 (m, 1H),1.80 (br s, 1H), 3.04 (m, 1H), 3.40 (m, 2H), 3.48 (m, 1H), 3.68 (s, 3H).

Intermediate 38 Methyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate

To a solution of 4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 27, 2.5 g, 15.82 mmol) and methyl(3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.72g, 15.82 mmol) in dichloromethane (200 mL) were added HOBt (2.42 g,15.82 mmol) and N-methyl morpholine (5.2 mL, 47.46 mmol). The reactionmixture was stirred for 1 h at room temperature and EDC HCl (5.43 g,28.47 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The reaction was quenched with the additionof 2N HCl (120 mL). The organic layer was washed with sodium bicarbonate(150 mL), water (150 mL), and brine, dried over anhydrous sodiumsulphate, filtered, concentrated under vacuum. Purification by columnchromatography (silica, 35% ethylacetate in petroleum ether) affordedmethyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate2.2 g (46%) as brown solid.

Mass (APCI): m/z 314.0 (M+H)

¹H NMR (400 MHz, DMSO-d₆): δ 0.83 (s, 3H), 1.54 (m, 1H), 1.66 (m, 1H),2.18 (s, 3H), 3.58 (m, 2H), 3.52 (m, 1H), 3.67 (s, 3H), 4.12 (m, 1H),6.90 (s, 1H), 7.54 (d, 1H), 11.56 (s, 1H).

Intermediate 394-Chloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of methyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate(Intermediate 38, 2.2 g, 7.05 mmol), potassium hydroxide (2.76 g, 49.35mmol), and hydrazine hydrate (2.5 mL, 49.35 mmol) in ethylene glycol(150 mL) was stirred for 40 h at 120° C. The reaction mixture was pouredin to water (120 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, concentrated in vacuo to yield the crude product which wastriturated with water (30 mL) to afford4-chloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide950 mg (52%) as brown solid.

MASS (APCI): m/z 256.0 (M+H)

¹H NMR (400 MHz, DMSO-d₆): δ 0.93 (d, 3H), 1.39 (m, 1H), 1.59 (m, 1H),1.88 (br s, 1H), 2.17 (s, 3H), 2.68 (m, 3H), 2.89 (m, 1H), 4.01 (m, 1H),6.89 (s, 1H), 7.42 (d, 1H), 11.52 (s, 1H).

Intermediate 40 Methyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate

To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(WO2006087543. 2.8 g, 14.53 mmol) and methyl(3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.5g, 14.53 mmol) in dichloromethane (200 mL) was added HOBT (2.22 g, 14.53mmol) and N-methyl morpholine (4.82 mL, 43.60 mmol). The reactionmixture was stirred for 1 h at room temperature and EDC HCl (5.12 g,26.16 mmol) was added. The resulting reaction mixture was stirred atroom temperature overnight. The reaction mixture was quenched with 2Nhydrochloric acid (120 mL). The organic layer was washed with sodiumbicarbonate (150 mL), water (150 mL), and brine, dried over anhydroussodium sulphate, filtered, concentrated under vacuum. Purification bycolumn chromatography (silica, 35% ethylacetate in pet ether) affordedmethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate3.4 g (67%) as brown solid.

MASS (APCI): m/z 348.0 (M+H).

¹H NMR (400 MHz, DMSO-d₆): δ 0.85 (d, 3H), 2.01 (m, 2H), 2.18 (s, 3H),3.39 (m, 4H), 3.52 (s, 3H), 4.16 (m, 1H), 7.05 (d, 1H), 12.01 (s, 1H).

Intermediate 413,4-Dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of methyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate(Intermediate 40, 3.4 g, 9.79 mmol), potassium hydroxide (3.84 g, 68.58mmol), and hydrazine hydrate (3.6 mL, 68.58 mmol) in ethylene glycol(180 mL) was stirred for 60 h at 120° C. The reaction mixture was pouredin to water (300 mL) and extracted with ethyl acetate (2×300 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, concentrated under vacuum to yield the crude product, whichwas triturated with water (150 mL) to afford3,4-dichloro-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide1.8 g, (63%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.86 (d, 3H), 1.88 (br s, 1H), 2.01 (br s,1H), 2.18 (s, 3H), 2.69 (m, 4H), 4.11 (br s, 2H), 6.90 (d, 1H).

Intermediate 42 Methyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate

To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 16, 2.12 g, 0.02 mol) and methyl(3S,4R)-4-amino-3-methylpiperidine-1-carboxylate (Intermediate 37, 2.0g, 0.02 mol) in dichloromethane (200 mL) was added HOBt (1.77 g, 0.02mol) and N-methyl morpholine (3.8 mL, 0.03 mol) and then the mixture wasstirred for 1 h at room temperature. EDC HCl (3.98 g, 0.0208 mol) wasadded to the reaction mixture and stirred at room temperature overnight.The reaction mixture was added to 2N hydrochloric acid (200 mL). Theorganic layer was washed with sodium bicarbonate (200 mL), water (250mL), and brine. The organic layer was dried over anhydrous sodiumsulphate, filtered, concentrated under vacuum to get methyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate3.3 g (72%) as white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.84 (d, 3H), 1.63 (br s, 2H), 2.00 (br s,1H), 2.21 (s, 3H), 3.30 (s, 3H), 3.59 (s, 9H), 4.13 (br s, 1H), 7.78 (d,1H), 12.55 (s, 1H).

LC-MS: m/z 338.9 (M+H).

Intermediate 434-Chloro-3-cyano-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of methyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidine-1-carboxylate(Intermediate 42, 3.3 g, 8.39 mmol), potassium hydroxide (3.3 g, 58.77mmol), and hydrazine hydrate (2.97 mL, 58.77 mmol) in ethylene glycol(200 mL) was stirred for 48 h at 120° C. The reaction mixture was pouredin to water (200 mL), then extracted with ethyl acetate (2×250 mL). Thecombined organic layers were dried over anhydrous sodium sulphate,filtered, concentrated under vacuum to yield the crude product, whichwas triturated with water (100 mL) to afford4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-methylpiperidin-4-yl]-1H-pyrrole-2-carboxamide1.5 g (63%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.88 (d, 3H), 1.67 (br s, 2H), 1.98 (m,1H), 2.21 (s, 3H), 2.79 (m, 4H), 2.92 (m, 1H), 4.09 (br s, 1H), 7.53 (d,1H).

MASS (APCI): 281.0 (M+H).

Intermediate 44 5-Chloropyrazine-2-carboxylic acid

5-Hydroxypyrazine-2-carboxylic acid (1.0 g, 0.007 mol) was taken inthionyl chloride (10 mL), to this solution dimethylformamide (0.1 mL)was added which was heated to reflux for 16 h. After this period, excessthionyl chloride was distilled off to get crude compound, which wasadded to ice (20 g) and extracted with ethyl acetate (2×70 mL). Theorganic layers were combined and dried over anhydrous sodium sulphateand concentrated under reduced pressure to obtain brown solid which wastriturated with diethyl ether (30 mL) to afford 600 mg (75%) of5-chloropyrazine-2-carboxylic acid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.94 (s, 1H), 9.04 (s, 1H), 13.92 (s, 1H).

Mass (APCI): m/z 157.0 (M−H).

Intermediate 45 Ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate

5-Chloropyrazine-2-carboxylic acid (Intermediate 44, 21 g, 0.132 mol)was taken in thionyl chloride (100 mL) which was heated to reflux for 2h and excess thionyl chloride was distilled off under reduced pressureto obtain a residue, which was dissolved in dry tetrahydrofuran (100mL). In another round bottom flask ethyl hydrogen malonoate (15.8 g,0.132 mol) was dissolved in tetrahydrofuran (500 mL) which was cooled to0° C. To the resulting solution was added methyl magnesium bromide (88mL, 0.265 M) and stirred the reaction mixture was stirred for 30 minbefore triethylamine (39.9 g, 0.396 M) was added. To this reactionmixture the above prepared acid chloride mixture was added, stirred for2 h at room temperature and tetrahydrofuran was evaporated from thereaction mixture and the water (500 mL) was added and extracted withethyl acetate (2×200 mL). The organic layers were combined and driedover anhydrous sodium sulphate, concentrated under reduced pressure toget obtain crude product which was purified by flash columnchromatography (10% ethyl acetate/pet ether) to afford 16.0 g (53.16%)of ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate white solid.

¹H NMR (400 MHz, CDCl₃): δ 1.26 (t, 3H), 1.28 (t, 3H), 4.18 (s, 2H),4.20 (q, 2H), 4.30 (q, 2H), 6.28 (s, 1H), 8.57 (s, 1H), 8.61 (s, 1H),8.89 (s, 1H), 9.04 (s, 1H), 12.35 (s, 1H).

Mass (APCI): m/z 227 (M−H).

Intermediate 46 Ethyl2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate

Ethyl 3-(5-chloropyrazin-2-yl)-3-oxopropanoate (Intermediate 45, 2.0 g,8.77 mM) was dissolved in ethyl acetate (30 mL), to this amberlyst resin(2.0 g) and N-iodosuccinamide (2.1 g, 9.64 mM) were added and stirredfor 1 h at room temperature. The resin was filtered and the filtrate wasconcentrated under reduced pressure to afford crude compound, which wasdissolved in methanol (25 mL). Thiourea (0.99 g, 13.15 mM) was added tothe reaction mixture and the reaction mixture was heated to reflux for 2h. The methanol was concentrated under reduced pressure and theresulting residue was partitioned between sodium bicarbonate solution(50 mL) and extracted with ethyl acetate (50 mL). The organic layerswere combined and dried over anhydrous sodium sulphate, filtered,concentrated under reduced pressure to obtain crude compound which waspurified by flash column chromatography (gradient up to 50% of ethylacetate/pet ether) to afford 500 mg (20.06%) of ethyl2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate off-whitesolid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.08 (t, 3H), 4.12 (q, 2H), 8.02 (s, 2H),8.72 (s, 1H), 8.84 (s, 1H).

Mass (APCI): m/z 285.0 (M+H).

Intermediate 47 Ethyl2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate

To a 0° C. solution of copper bromide (238 mg, 1.056 mM) in acetonitrile(30 mL) was added tert-butyl nitrite (87 mg, 0.845 mM) and the reactionmixture was stirred 30 min followed by addition of ethyl2-amino-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate(Intermediate 46, 200 mg, 0.704 mM). The reaction mixture was stirredfor 2 h at room temperature. Acetonitrile was removed from the reactionmixture by distillation and then water (50 mL) was added. The reactionmixture was extracted with diethyl ether (2×50 mL). The organic layerswere combined and dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to obtain crude product which waspurified by flash column chromatography (gradient up to 10% of ethylacetate/pet ether) to afford 50 mg (20.4%) of ethyl2-bromo-4-(5-chloropyrazin-2-yl)-1,3-thiazole-5-carboxylate as off whitesolid.

¹H NMR (400 MHz, CDCl₃): δ 1.34 (t, 3H), 4.38 (q, 2H), 8.68 (s, 1H),8.84 (s, 1H).

Mass (APCI): m/z 349.9 (M+H).

Intermediate 48 Ethyl 2-hydroxypropanoate

To a stirred solution of 2-hydroxypropanenitrile (50 g, 704 mmol) indiethylether (300 mL) was added dry ethanol (51 mL, 774 mmol). To theabove reaction mixture HCl gas was passed at −5° C. for 2 h. and stirredat room temperature for 16 h. The solid that formed was collected byfiltration and washed with diethyl ether (200 mL) to obtain ethyl2-hydroxypropanoate 75 g (90%) as white solid.

¹H NMR (400 MHz, DMSO-d6): δ 1.38 (t, 3H), 4.49 (q, 1H), 6.55 (br s,1H).

MASS (APCI +ve Scan): m/z 117 (M+H).

Intermediate 49 2-Hydroxypropanamide

To a stirred solution of ethyl 2-hydroxypropanoate (Intermediate 48, 237g, 1549 mmol) in dry ethanol (1000 mL) ammonia gas was passed for 90 minat −5° and stirred at room temperature for another 16 h. The solid thatformed was collected by filtration and washed with diethyl ether (200mL) to obtain 2-hydroxypropanamide 145 g (75%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 1.35 (d, 3H), 4.49 (q, 1H), 6.25 (br s,1H), 8.60 (br s, 3H).

MASS (APCI +ve Scan): m/z 89 (M+H).

Intermediate 50 2-(1-Hydroxyethyl)pyrimidin-4(3H)-one

To a stirred solution of ethyl 3-oxopropanoate (Intermediate 49, 3.4 g,24.18 mmol) in water (4 mL), a solution of 2-hydroxypropanamide (1 g8.06 mmol) in water (4 mL) was added dropwise at 10° C. and stirred atroom temperature for 18 h. The reaction mixture was cooled to 0° C. andthe pH was adjusted to 7 using acetic acid (3 mL). The aqueous layer wasextracted with n-butanol (2×40 mL). The organic layer was dried andconcentrated under reduced pressure to obtain2-(1-hydroxyethyl)pyrimidin-4(3H)-one 0.75 g (66.9%).

¹H NMR (400 MHz, DMSO-d₆): δ 1.30 (d, 3H), 4.50 (q, 2H), 6.10 (d, 1H),7.80 (d, 1H).

Intermediate 51 2-Acetylpyrimidin-4(3H)-one

To a stirred solution of 2-(1-hydroxyethyl)pyrimidin-4(3H)-one(Intermediate 50, 5 g, 35.71 mmol) in dichloroethane (200 mL), manganesedioxide (31 g, 357.1 mmol) was added. The reaction mixture was heated to90° C. for 5 h. The reaction mixture was filtered through a celite bedand washed with dichloroethane (60 mL). The filtrate was concentrated todryness to yield 1.6 g (32.6%) 2-acetylpyrimidin-4(3H)-one.

¹H NMR (400 MHz, DMSO-d₆): δ 2.50 (s, 3H), 6.50 (d, 1H), 8.05 (d, 1H),12.60 (s, 1H).

LC-MS: m/z 138 (M+H).

Intermediate 52 1-[4-(Piperidin-1-yl)pyrimidin-2-yl]ethanone

To a stirred solution of 2-acetylpyrimidin-4(3H)-one (Intermediate 51,500 mg, 3.62 mmol) in dichloromethane (10 mL) cooled to 0° C., pyridine(860 mg, 10.87 mmol) was added and stirred for 10 min at 0° C., followedby the addition of methane sulfonyl chloride (830 mg, 7.23 mmol) at 0°C. The above reaction mixture was stirred at room temperature forovernight. The reaction mixture was washed with water (50 mL), theaqueous layer was extracted with dichloromethane (50 mL). The combinedorganic layer was washed with brine solution, dried over anhydroussodium sulphate and concentrated under reduced pressure. The cruderesidue was dissolved in acetonitrile; piperidine (616 mg, 7.24 mmol)was added and the reaction mixture was stirred for 2 h at roomtemperature. The reaction mixture was concentrated under reducedpressure; water (50 mL) was added and extracted with ethyl acetate (2×30mL). The combined organic layer was washed with brine and dried overanhydrous sodium sulphate and concentrated under reduced pressure toyield the crude product, which was purified by column chromatographyover silica gel (10-50% ethyl acetate/pet ether) to obtain1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone 200 mg (46.8%).

¹H NMR (400 MHz, CDCl₃): δ 1.61 (m, 6H), 2.66 (s, 3H), 3.68 (m, 4H),6.56 (d, 1H), 8.31 (d, 1H).

LC-MS: m/z 204 (M+H).

Intermediate 53-56

The following Intermediates were prepared according to the proceduredescribed for Intermediate 52 from the starting materials indicated inthe table.

Int Compound Data SM 53 1-[4-(morpholin-4- yl)pyrimidin-2- yl]ethanone

¹H NMR (400 MHz, CDCl₃) δ 2.68 (s, 3H), 3.70 (m, 4H), 3.81 (m, 4H), 6.57(d, 1H), 8.39 (d, 1H). MASS (APCI +ve Scan): m/z 208 (M + H)Intermediate 51 and morpholine 54 1-[4-(4- methylpiperazin-1-yl)pyrimidin-2- yl]ethanone

¹H NMR (400 MHz, CDCl₃): δ 2.33 (s, 3H), 2.50 (m, 4H), 2.68 (s, 3H),3.73 (m, 4H), 6.58 (d, 1H), 8.34 (d, 1H), LC-MS: m/z 221.49 (M + H)Intermediate 51 and methylpiperazine 55 1-{4-[4-(2-methylpropyl)piperazin- 1-yl]pyrimidin-2- yl}ethanone

¹H NMR (400 MHz, CDCl₃): δ 0.92 (m, 6H), 1.81 (m, 1H), 2.12 (d, 2H),2.48 (t, 4H), 2.68 (s, 3H), 3.71 (m, 4H), 6.56 (d, 1H), 8.34 (d, 1H)MASS (APCI +ve Scan): m/z 263.1 (M + H). Intermediate 51 and 2-methylpropylpiperazine 56 1-[4-(4-ethylpiperazin- 1-yl)pyrimidin-2-yl]ethanone

¹H NMR (400 MHz, CDCl₃): δ 1.13 (t, 3H), 2.54 (m, 6H), 2.68 (s, 3H),3.74 (bs, 4H), 6.58 (d, 1H), 8.36 (d, 1H). MASS (APCI +ve Scan): m/z 235(M + H) Intermediate 51 and ethylpiperazine

Intermediate 57 Methyl3-oxo-3-[4-(piperidin-1-yl)pyrimidin-2-yl]propanoate

To a stirred solution of 1-[4-(piperidin-1-yl)pyrimidin-2-yl]ethanone(Intermediate 52, 0.6 g, 2.92 mmol) in dimethylcarbonate (10 mL), sodiumhydride (0.281 g, 11.7 mmol, 60%) was added portion wise at 0-5° C. overa period of 10 min. The reaction mixture was heated to 90° C. for 4 h.The reaction mixture was quenched by adding ice water. The aqueous layerpH was adjusted to neutral with dilute HCl, the aqueous layer wasextracted with ethyl acetate (2×50 mL). The organic layer was dried andconcentrated. The crude product was purified by column chromatography(75% ethylacetate & pet ether) to obtain methyl3-oxo-3-[4-(piperidin-1-yl)pyrimidin-2-yl]propanoate 0.4 g (52%).

¹H NMR (400 MHz, CDCl₃): δ 1.65 (m, 6H), 3.67 (bs, 4H), 3.71 (s, 3H),4.06 (s, 3H) 6.57 (d, 1H), 8.31 (d, 1H).

MASS (APCI +ve Scan): m/z 264 (M+H).

Intermediate 58-61

The following Intermediates were prepared according to the proceduredescribed for Intermediate 57 from the starting materials indicated inthe table.

Int Compound Data SM 58 Methyl 3-[4-(morpholin-4- yl)pyrimidin-2-yl]-3-oxopropanoate

MASS (APCI +ve Scan): m/z 266 (M + H). Intermediate 53 59 Methyl3-[4-(4-methylpiperazin- 1-yl)pyrimidin-2-yl]-3- oxopropanoate

MASS (APCI +ve Scan): m/z 279 (M + H) Intermediate 54 60 Methyl3-{4-[4-(2- methylpropyl)piperazin-1- yl]pyrimidin-2-yl}-3-oxopropanoate

MASS (APCI +ve Scan): m/z 320.9 (M + H) Intermediate 55 61 Methyl3-[4-(4-ethylpiperazin- 1-yl)pyrimidin-2-yl]-3- oxopropanoate

MASS (APCI +ve Scan): m/z 293 (M + H) Intermediate 56

Intermediate 62 Methyl2-amino-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate

To a stirred solution of methyl3-oxo-3-[4-(piperidin-1-yl)pyrimidin-2-yl]propanoate (Intermediate 57,0.4 g, 1.52 mmol) in ethyl acetate (20 mL), N-iodosuccinamide (0.374 g,1.672 mmol) and Amberlyst resin-15 (0.40 g) were added. The reactionmixture was stirred at room temperature for 30-40 min. The reactionmixture was filtered and the filtrate was concentrated to dryness. Theobtained crude (iodo compound) was dissolved in methanol (20 mL) andthiourea (0.138 g, 1.852 mmol) was added. The reaction mixture wasstirred at room temperature for 1 h. The reaction mixture wasconcentrated to dryness. The residue was basified with saturated sodiumbicarbonate solution (20 mL). The aqueous layer was extracted with ethylacetate (2×50 mL). The combined organic layer was dried and concentratedto obtain the crude which was purified by prep HPLC to obtain methyl2-amino-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate0.080 g (16.5%)

¹H NMR (400 MHz, DMSO-d₆): δ 1.61 (d, 6H), 3.68 (s, 3H), 3.84 (bs, 4H),7.22 (d, 1H), 8.19 (d, 1H), 8.35 (d, 1H).

LC-MS: m/z 320 (M+H).

Intermediate 63-66

The following Intermediates were prepared according to the proceduredescribed for Intermediate 62 from the starting materials indicated inthe table.

Int Compound Data SM 63 Methyl 2-amino-4-[4- (morpholin-4-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 3.67 (s, 3H), 3.73 (t, 4H), 3.85 (t, 4H),7.19 (d, 1H), 8.16 (bs, 4H), 8.41 (d, 1H). LC-MS: m/z 322.4 (M + H).Intermediate 58 64 Methyl 2-amino-4-[4-(4-methylpiperazin-1-yl)pyrimidin- 2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 2.21 (s, 3H), 2.36 (bs, 4H), 3.30 (s, 3H),3.58 (bs, 4H), 6.79 (d, 1H), 7.80 (bs, 2H), 8.21 (d, 1H). MASS (APCI +veScan): m/z 335 (M + H) Intermediate 59 65 methyl 2-amino-4-{4-[4-(2-methylpropyl)piperazin-1- yl]pyrimidin-2-yl}-1,3-thiazole- 5-carboxylate

MASS (APCI +ve Scan): m/z 377.1 (M + H) Intermediate 60 66 Methyl2-amino-4-[4-(4- ethylpiperazin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate

¹H NMR (400 MHz, DMSO-d₆): δ 1.02 (t, 3H), 2.40 (bs, 4H), 3.32 (s, 3H),3.55 (bs, 4H), 3.32 (s, 3H), 3.55 (bs, 4H), 6.78 (d, 1H), 7.83 (s, 2H),8.21 (d, 1H), MASS (APCI +ve Scan): m/z 349.41 (M + H) Intermediate 61

Intermediate 67 Methyl2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate

To a stirred solution of methyl2-amino-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate(Intermediate 62, 0.070 g, 0.219 mmol) in concentrated HCl (1 mL),sodium nitrite (0.045 g, 0.658 mmol) in water (1 mL) was added drop wiseat 0° C. The reaction mixture was stirred at room temperature for 30min. The reaction mixture was cooled to 5-10° C. and basified withsaturated sodium bicarbonate solution (20 mL). The aqueous layer wasextracted with ethyl acetate (2×30 mL). The combined organic layer waswashed with brine solution, dried and concentrated under reducedpressure to obtain methyl2-chloro-4-[4-(piperidin-1-yl)pyrimidin-2-yl]-1,3-thiazole-5-carboxylate0.040 g (54%).

¹H NMR (400 MHz, CDCl₃): δ 1.60 (d, 6H), 3.62 (bs, 4H), 3.80 (s, 3H),6.46 (d, 1H), 8.27 (d, 1H).

MASS (APCI +ve Scan): m/z 339 (M+H).

Intermediate 68-71

The following Intermediates were prepared according to the proceduredescribed for Intermediate 67 from the starting materials indicated inthe table.

Int Compound Data SM 68 Methyl 2-chloro-4-[4- (morpholin-4-yl)pyrimidin-2-yl]-1,3- thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 3.66 (t, 3H), 3.77 (t, 4H), 3.81 (s, 3H),6.51 (d, 1H), 8.35 (d, 1H), MASS (APCI +ve Scan): m/z 341 (M + H)Intermediate 63 69 methyl 2-chloro-4-[4-(4- methylpiperazin-1-yl)pyrimidin-2-yl]-1,3- thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 2.34 (s, 3H) 2.48 (t, 4H), 3.68 (bs, 4H),3.81 (s, 3H), 6.51 (d, 1H), 8.33 (d, 1H), MASS (APCI +ve Scan): m/z354.1 (M + H) Intermediate 64 70 Methyl 2-chloro-4-{4-[4-(2-methylpropyl)piperazin-1- yl]pyrimidin-2-yl}-1,3- thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 0.92 (m, 6H), 2.10 (d, 3H), 2.45 (t, 4H),3.65 (bs, 4H), 3.81 (s, 3H), 6.48 (d, 1H), 8.29 (d, 1H) MASS (APCI +veScan): m/z 395.8 (M + H) Intermediate 65 71 Methyl 2-chloro-4-[4-(4-ethylpiperazin-1- yl)pyrimidin-2-yl]-1,3- thiazole-5-carboxylate

¹H NMR (400 MHz, CDCl₃): δ 1.12 (t, 3H), 2.47 (m, 6H), 3.69 (bs, 4H),3.81 (s, 3H), 6.49 (s, 3H), 6.49 (d, 1H), 8.33 (d, 1H). MASS (APCI +veScan): m/z 368 (M + H) Intermediate 66

Intermediate 72ethyl-(3S,4R)-4-[(tert-butoxycarbonyl)amino]-3-(propyoxypiperidine-1-carboxylate

Chiral HPLC purification ofCis(±)ethyl-4-[(tert-butoxycarbonyl)amino]-3-(propyoxypiperidine-1-carboxylate(WO2006087543, Chiralpak AD, 70% hexane/30% 1:1 ethanol:methanol/0.1%diethylamine, flow rate 120 mL/min) provided 2 g of the desired product.

NMR□: 0.94 (m, 3H), 1.25 (m, 3H), 1.43 (s, 9H), 1.53 (m, 2H), 1.71 (m,1H), 3.04 (m, 2H), 3.37 (m, 2H), 3.50 (m, 2H), 3.69 (m, 1H), 3.89 (m,1H), 4.15 (m, 2H), 6.5 (d, 1H).

Intermediate 73 Ethyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate

Ethyl-(3S,4R)-4-[(tert-butoxycarbonyl)amino]-3-(propyoxypiperidine-1-carboxylate(Intermediate 72, 3 g) was treated with TFA (5 mL) for 30 min and theconcentrated under reduced pressure. The resulting residue was dissolvedin dichloromethane (150 mL) with4-chloro-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 27, 1.45 g,9.13 mmol), HOBT (1.676 g, 10.95 mmol) and N-methyl morpholine (2.76 g,27.39 mmol). The reaction mixture was stirred for 1 h at roomtemperature and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (3.02 g, 16.43 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The reaction mixturewas quenched with 2N hydrochloric acid (30 mL) and the layers wereseparated. The organic layer was washed with sodium bicarbonate (40 mL),water (60 mL) and finally with brine successively and dried overanhydrous sodium sulphate, filtered, and concentrated under vacuum toafford ethyl(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate2.8 g (84%) as solid.

¹H NMR (400 MHz, CDCl₃) δ 0.95 (t, 3H), 1.22 (t, 3H), 1.65 (m, 6H), 2.21(s, 3H), 2.81 (m, 2H), 3.21 (m, 2H), 3.4 (m, 3H), 3.71 (m, 1H), 4.4 (m,1H), 6.21 (d, 1H), 9.91 (s, 1H)

LC-MS: m/z 372.3 (M+H).

Intermediate 744-Chloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of ethyl(3R,4S)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate(Intermediate 73, 2.8 g, 7.547 mmol) potassium hydroxide (4.2 g, 75.47mmol), and Hydrazine hydrate (3.6 mL, 75.47 mmol) in ethylene glycol(100 mL) was stirred for 60 h at 120° C. The reaction mixture was pouredinto water (300 mL) and extracted with ethyl acetate (2×300 mL). Thecombined organic extracts were dried over anhydrous sodium sulphate,filtered, and concentrated under vacuum to afford4-chloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide650 mg, 30% as solid.

¹H NMR (400 MHz, CDCl₃): δ 0.98 (t, 3H), 1.62 (m, 4H), 2.21 (t, 3H),2.61 (m, 2H), 3.12 (m, 2H), 3.32 (m, 1H), 3.61 (m, 2H), 4.15 (m, 1H),6.21 (d, 1H), 6.4 (s, 1H), 9.45 (s, 1H).

LC-MS: m/z 300.2 (M+H).

Intermediate 75 Ethyl(3R,4S)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate

To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid(Intermediate 16, 2 g, 8.69 mmol) and ethyl(3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73,1.59 g, 8.695 mmol) in dichloromethane (150 mL) was addedN-Hydroxybenzotriazole (1.6 g, 10.43 mM) and N-methylmorpholine (2.63 g,26.08 mmol). The reaction mixture was stirred for 1 h at roomtemperature and 1-Ethyl-3-(3-dimethyl amino propyl)carbodiimidehydrochloride (2.87 g, 15.6 mM) was added. The resulting reactionmixture was stirred at room temperature overnight. The reaction mixturewas quenched with 2N hydrochloric acid (50 mL) and the layers wereseparated. The organic layer was washed with sodium bicarbonate (40 mL),water (60 mL) and finally with brine successively and dried overanhydrous sodium sulphate, filtered, concentrated under vacuum to affordethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate2.6 g (76%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.95 (t, 3H), 1.25 (t, 3H), 1.75 (m, 4H),2.30 (s, 3H), 2.97 (m, 3H), 3.49 (m, 2H), 4.01 (m, 3H), 4.13 (m, 2H),7.21 (d, 1H), 11.19 (s, 1H).

MASS: m/z 397.1 (M+H).

Intermediate 764-Chloro-3-cyano-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of ethyl(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate(Intermediate 75, 2.6 g, 6.56 mmol), potassium hydroxide (3.67 g, 65.6.mmol), and hydrazine hydrate (3.28 g, 65.6 mmol) in ethylene glycol (100mL) was stirred for 60 h at 120° C. The reaction mixture was cooled toroom temperature and poured into water (75 mL) and extracted with ethylacetate (2×100 mL). The combined organic extracts were dried overanhydrous sodium sulphate, filtered, concentrated under vacuum to afford4-chloro-3-cyano-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide1.5 g, 71% as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.95 (t, 3H), 1.75 (m, 4H), 2.30 (m, 1H),2.62 (m, 2H), 3.12 (m, 2H), 3.30 (m, 3H), 3.42 (m, 2H), 3.55 (m, 1H),4.19 (m, 1H), 7.19 (m, 1H).

LC-MS: m/z 325.2 (M+H).

Intermediate 77 Ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate

To a solution of 3,4-dichloro-5-methyl-1H-pyrrole-2-carboxylic acid(WO2006087543, 1.77 g, 9.13 mmol) and ethyl(3S,4R)-4-amino-3-propoxypiperidine-1-carboxylate (see Intermediate 73,2.1 g, 9.13 mmol) in dichloromethane (150 mL) was addedN-Hydroxybenzotriazole (1.67 g, 10.95 mmol) and N-methylmorpholine (2.76g, 27.39 mmol). The reaction mixture was stirred for 1 h at roomtemperature and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (3.023 g, 16.43 mmol) was added. The resulting reactionmixture was stirred at room temperature overnight. The reaction mixturewas quenched with 2N hydrochloric acid (30 mL) and the layers wereseparated. The organic layer was washed with sodium bicarbonate (40 mL),water (60 mL) and finally with brine successively, and dried overanhydrous sodium sulphate, filtered, and concentrated under vacuum toafford ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate3.3 g (89.1. %) as solid.

¹H NMR (400 MHz, CDCl₃): δ 0.95 (t, 3H), 1.30 (t, 3H), 1.60 (m, 2H),1.80 (m, 2H), 2.22 (s, 3H), 3.90 (m, 2H), 3.25 (m, 1H), 3.42 (m, 1H),3.65 (m, 1H), 4.22 (m, 4H), 4.41 (m, 1H). 7.21 (d, 1H), 9.91 (m, 1H).

LCMS: m/z 407.3 (M+H).

Intermediate 783,4-Dichloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide

A solution of ethyl(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-propoxypiperidine-1-carboxylate(Intermediate 77, 3.3 g, 8.12 mmol) potassium hydroxide (4.55 g, 81.2mmol), and hydrazine hydrate (4.06 g, 81.2 mmol) in ethylene glycol (100mL) was stirred for 60 h at 120° C. The reaction mixture was cooled toroom temperature and poured into water (300 mL) and extracted with ethylacetate (2×300 mL). The combined organic extracts were dried overanhydrous sodium sulphate, filtered, and concentrated under vacuum toafford3,4-dichloro-5-methyl-N-[(3S,4R)-3-propoxypiperidin-4-yl]-1H-pyrrole-2-carboxamide1.5 mg, (62.5%) as solid.

¹H NMR (400 MHz, DMSO-d₆): δ 0.95 (t, 3H), 1.59 (m, 4H), 2.20 (s, 3H),2.51 (m, 4H), 2.80 (m, 2H), 3.25 (m, 1H), 3.51 (m, 1H), 4.01 (m, 1H),7.05 (d, 1H).

LC-MS: m/z 334.2 (M+H).

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ is chloro orcyano; R² is hydrogen, chloro, or cyano; R³ is halo, C₁₋₄alkyl,C₁₋₄alkoxy, or allyloxy; R⁴ is hydrogen or C₁₋₄alkyl; Ring A is selectedfrom formula (a), (b) or (b′):

wherein: “*” is the point of attachment to the thiazolyl ring; X is CH,CR⁶, or N; R⁵ is H, a C₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl; R⁶, for eachoccurrence is independently selected from halo, —NR⁷R⁸, —OR⁸, andheterocycle wherein said heterocycle comprises at least one nitrogenring member and is optionally substituted on one or more carbon atomswith one or more R⁹ and is optionally substituted on one or more ringnitrogens with R¹⁰; R^(6′) is hydrogen or R⁶; R⁷ and R⁸ are each,independently, selected from the group consisting of hydrogen and aC₁₋₆alkyl wherein said alkyl is optionally substituted with one or moreindependently selected from —OH, N,N-di(C₁₋₄alkyl)amino, a C₁₋₆alkoxy, aC₁₋₆alkoxyC₁₋₆alkoxy, and heterocycle, wherein said heterocycle isoptionally substituted on one or more carbon atoms with one or moreindependently selected halo, C₁₋₆alkyl, and C₁₋₆alkoxy, and wherein ifsaid heterocyclyl contains an —NH— moiety that nitrogen may beoptionally substituted by a C₁₋₄alkyl; R⁹ is, for each occurrence, isindependently selected from a C₁₋₄alkyl, halo, hydroxy, C₁₋₄alkoxy,amino, N—(C₁₋₄alkyl)amino, and N,N-di(C₁₋₄alkyl)amino; R¹⁰, for eachoccurrence, is independently selected from a C₁₋₄alkyl optionallysubstituted with N,N-di(C₁₋₄alkyl)amino, —OH, heterocycle, andC₃₋₆cycloalkyl, wherein the heterocycle may be optionally substitutedwith C₁₋₄alkyl; and n is 0, 1, 2, or
 3. 2. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein Ring A is representedby formula (a).
 3. The compound of claim 2, or a pharmaceuticallyacceptable salt thereof, wherein X is CR^(6′).
 4. The compound of claim2, or a pharmaceutically acceptable salt thereof, wherein X is N.
 5. Thecompound of claim 2, or a pharmaceutically acceptable salt thereof,wherein Ring A is selected from the group consisting of1-(2-methoxyethyl)-1H-imidazol-2-yl or 1-methyl-1H-1,2,4-triazol-5-yl.6. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein Ring A is represented by formula (b).
 7. The compoundof claim 6, or a pharmaceutically acceptable salt thereof, wherein X isCH or CR⁶.
 8. The compound of claim 6, or a pharmaceutically acceptablesalt thereof, wherein X is N.
 9. The compound of claim 6, or apharmaceutically acceptable salt thereof, wherein Ring A is selectedfrom the group consisting of 3-fluoropyridin-2-yl or pyrazin-2-yl. 10.The compound of claim 6, wherein n is 1 and R⁶ is piperidino,piperazinyl, N-methylpiperazino or morpholino.
 11. The compound of claim6, wherein n is 1 and R⁶ is selected from1-(1H-1,2,3-triazol-5-yl)methanamino, 2-(2-oxo-pyrrolidino)ethylamino,2-methoxyethylamino, 2-(4-fluoropiperidino)ethylamino,1-(1,3-dioxan-4-yl)-N-methylmethanamino,N-(1-methoxymethyl-2-methoxyethyl)amino,2-(2-oxo-1,3-oxazolidin-3-yl)-ethylamino,2-(2-methoxyethoxy)-ethylamino, 4-[2-(diethylamino)ethyl]piperazin-1-yl,2-(4-methylpiperazin-1-yl)ethylamino, 2-(dimethylamino)ethoxy,2-(4-methylpiperazin-1-yl)ethoxy, 2-morpholinoethylamino, or2-(2-oxo-imidazolidin-1-yl)ethylamino.
 12. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R¹ is chloro.
 13. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R² is hydrogen.
 14. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R² is chloro.
 15. Thecompound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R³ is selected from methyl, methoxy, ethoxy, or allyloxy. 16.The compound of claim 1, or a pharmaceutically acceptable salt thereof,wherein R⁴ is hydrogen.
 17. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein R⁴ is methyl or ethyl.18. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: R¹ is chloro; R² is hydrogen, chloro or cyano; R³ ismethyl, ethoxy, or allyloxy; R⁴ is hydrogen, methyl or ethyl; Ring A is1-(2-methoxyethyl)-1H-imidazol-2-yl, 1-methyl-1H-1,2,4-triazol-5-yl,3-fluoropyridin-2-yl or pyrazin-2-yl.
 19. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is chloro; R² ishydrogen, chloro or cyano; R³ is methyl, ethoxy, or allyloxy; R⁴ ishydrogen, methyl or ethyl; Ring A is formula (c):

wherein: X is CH or N; and R⁵ is H, a C₁₋₄alkyl, or C₁₋₄alkoxyC₁₋₄alkyl.20. The compound of claim 1, or a pharmaceutically acceptable saltthereof, wherein: R¹ is chloro; R² is hydrogen, chloro or cyano; R³ ismethyl, ethoxy, or allyloxy; R⁴ is hydrogen, methyl or ethyl; Ring A isselected from formula (d) or (e):

wherein: X is CH or N; and R⁶ is a halo.
 21. The compound of claim 1, ora pharmaceutically acceptable salt thereof, wherein: R¹ is chloro; R² ishydrogen, chloro or cyano; R³ is methyl, methoxy, ethoxy, or allyloxy;R⁴ is hydrogen, methyl or ethyl; Ring A is selected from formula (d) or(e):

wherein: R⁶ is —OR⁸ or —NR⁷R⁸; R⁷ is hydrogen or a C₁₋₄alkyl; and R⁸ isselected from the group consisting of 1-(1H-1,2,3-triazol-5-yl)methyl,2-(2-oxo-pyrrolidino)ethyl, 2-methoxyethyl, 2-(4-fluoropiperidino)ethyl,1-(1,3-dioxan-4-yl)-N-methylmethyl, 1-methoxymethyl-2-methoxyethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(dimethylamino)ethyl,2-(4-methylpiperazin-1-yl)ethyl, 2-(2-oxo-1,3-oxazolidin-3-yl)-ethyl,2-(2-methoxyethoxy)-ethyl, 2-morpholinoethyl, or2-(2-oxo-imidazolidin-1-yl)ethyl.
 22. The compound of claim 1, or apharmaceutically acceptable salt thereof, wherein: R¹ is chloro; R² ishydrogen, chloro or cyano; R³ is methyl, methoxy, ethoxy, or allyloxy;R⁴ is hydrogen, methyl or ethyl; Ring A is selected from formula (d) or(e):

wherein: R⁶ is piperidino, piperazinyl, N-methylpiperazino ormorpholino.
 23. The compound of claim 21 or 22, or a pharmaceuticallyacceptable salt thereof, wherein R¹ and R² are both chloro; and R³ ismethoxy.
 24. A compound selected from the group consisting of:2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylicacid; Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylicacid;2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylicacid; Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-(prop-2-en-1-yloxy)piperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(3,4-dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(1-methyl-1H-1,2,4-triazol-5-yl)-1,3-thiazole-5-carboxylate;Methyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-[1-(2-methoxyethyl)-1H-imidazol-2-yl]-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(3-fluoropyridin-2-yl)-1,3-thiazole-5-carboxylate;Ethyl2-[(3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methylpiperidin-1-yl]-4-(pyrazin-2-yl)-1,3-thiazole-5-carboxylate;2-[(3R,4S)-4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl]-4-[5-(4-methylpiperazin-1-yl)pyrazin-2-yl]-1,3-thiazole-5-carboxylicacid; and pharmaceutically acceptable salts thereof.
 25. Apharmaceutical composition comprising a compound of claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient or carrier.
 26. A method of inhibiting bacterialDNA gyrase and/or bacterial topoisomerase IV in a warm-blooded animal inneed of such treatment, comprising administering to the animal aneffective amount of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 27. A method of producing an antibacterialeffect in a warm-blooded animal in need of such treatment, comprisingadministering to the animal an effective amount of a compound of claim1, or a pharmaceutically acceptable salt thereof.
 28. A method oftreating a bacterial infection in a warm-blooded animal in need thereof,comprising administering to the animal an effective amount of a compoundof claim 1, or a pharmaceutically acceptable salt thereof.
 29. Themethod of claim 28, wherein the bacterial infection is selected from thegroup consisting of community-acquired pneumoniae, hospital-acquiredpneumoniae, skin and skin structure infections, acute exacerbation ofchronic bronchitis, acute sinusitis, acute otitis media,catheter-related sepsis, febrile neutropenia, osteomyelitis,endocarditis, urinary tract infections and infections caused by drugresistant bacteria such as Penicillin-resistant Streptococcuspneumoniae, methicillin-resistant Staphylococcus aureus,methicillin-resistant Staphylococcus epidermidis andVancomycin-Resistant Enterococci.